Phosphatidylinositol 3-kinase inhibitors

ABSTRACT

The present disclosure provides phosphatidylinositol 3-kinase (PI3K) inhibitors of formula (I), 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts thereof, in which n, m, R 1 , R 2 , and R 3  are as defined herein. These compounds are useful for treatment of conditions mediated by one or more PI3K isoforms, such as PI3Kδ. The present disclosure further provides pharmaceutical compositions that include a compound of formula (I), or pharmaceutically acceptable salts thereof, and methods of using these compounds and compositions to treat conditions mediated by one or more PI3K isoforms, such as PI3Kδ.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/745,437, filed Dec. 21, 2012, the disclosure ofwhich is hereby incorporated by reference in its entirety.

FIELD

The present disclosure relates generally to inhibitors ofphosphatidylinositol 3-kinase (PI3K) activity and, more specifically, tonovel compounds that are selective inhibitors of PI3K delta activity.

BACKGROUND

Cell signaling via 3′-phosphorylated phosphoinositides has beenimplicated in a variety of cellular processes, e.g., malignanttransformation, growth factor signaling, inflammation, and immunity. Seegenerally Rameh et al., J. Biol. Chem., 274:8347-8350 (1999). The enzymeresponsible for generating these phosphorylated signaling products isphosphatidylinositol 3-kinase (PI 3-kinase; PI3K). PI3K originally wasidentified as an activity associated with viral oncoproteins and growthfactor receptor tyrosine kinases that phosphorylate phosphatidylinositol(PI) and its phosphorylated derivatives at the 3′-hydroxyl of theinositol ring. See Panayotou et al., Trends Cell Biol 2:358-60 (1992).

Presently, three classes of the PI 3-kinase (PI3K) enzymes aredistinguished, based on their substrate specificities. Class I PI3Ks canphosphorylate phosphatidylinositol (PI),phosphatidylinositol-4-phosphate, andphosphatidylinositol-4,5-biphosphate (PIP₂) to producephosphatidylinositol-3-phosphate (PIP),phosphatidylinositol-3,4-biphosphate, andphosphatidylinositol-3,4,5-triphosphate, respectively. Class II PI3Ksphosphorylate PI and phosphatidylinositol-4-phosphate, whereas Class IIIPI3Ks can only phosphorylate PI.

The initial purification and molecular cloning of PI 3-kinase revealedthat it was a heterodimer consisting of p85 and p110 subunits. See Otsuet al., Cell, 65:91-104 (1991); Hiles et al., Cell, 70:419-29 (1992).Since then, four distinct Class I PI3Ks have been identified, designatedPI3K α, β, δ, and γ, each consisting of a distinct 110 kDa catalyticsubunit and a regulatory subunit. More specifically, three of thecatalytic subunits, i.e., p110α, p110β, and p110 δ, each interact withthe same regulatory subunit, i.e., p85, whereas p110γ interacts with adistinct p101 regulatory subunit. As described below, the patterns ofexpression of each of these PI3Ks in human cells and tissues also aredistinct.

Identification of the p110δ isoform of PI 3-kinase is described inChantry et al., J. Biol. Chem., 272:19236-41 (1997). It was observedthat the human p110δ isoform is expressed in a tissue-restrictedfashion. It is expressed at high levels in lymphocytes and lymphoidtissues, suggesting that the protein might play a role in PI3-kinase-mediated signaling in the immune system. Details concerning thep110δ isoform also can be found in U.S. Pat. Nos. 5,858,753; 5,822,910;and 5,985,589, each of which is incorporated herein by reference. Seealso Vanhaesebroeck et al., Proc. Natl. Acad. Sci. USA, 94:4330-5(1997); and WO 97/46688.

A need remains, however, for additional therapeutic agents useful totreat proliferative disorders or diseases that are mediated by PI3K. Thepresent invention provides novel compounds that are inhibitors of PI3Kisoforms.

SUMMARY

Compounds and pharmaceutically acceptable salts thereof useful forinhibiting PI3K isoforms, such as PI3Kδ, are described herein.Compositions, including pharmaceutical compositions, and kits thatinclude the compounds are also provided, as are methods of using andmaking the compounds. The compounds provided herein may find use intreating diseases, disorders, or conditions that are mediated by PI3Kisoforms, such as PI3Kδ.

In one aspect, provided is a compound of formula (J):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein:

A is N or CH;

n is 0, 1, 2, or 3;

each R¹ is independently unsubstituted or substituted alkyl,unsubstituted or substituted haloalkyl, unsubstituted or substitutedaryl, unsubstituted or substituted heteroaryl, halo, cyano,NHC(═O)alkylene-N(R^(1x))₂, NO₂, OR^(1x), OCF₃, N(R^(1x))₂,OC(═O)R^(1x), C(═O)R^(1x), C(═O)OR^(1x), aryl-OR^(1y), Het,NR^(1x)C(═O)alkylene-C(═O)OR^(1x), aryl-O-alkylene-N(R^(1x))₂,aryl-O—C(═O)R^(1x), alkylene-C(═O)OR^(1x), O-alkylene-C(═O)OR^(1x),alkylene-O-alkylene-C(═O)OR^(1x), C(═O)NR^(1x)SO₂R^(1x),alkylene-N(R^(1x))₂, alkenylene-N(R^(1x))₂,C(═O)NR^(1x)-alkylene-OR^(1x), C(═O)NR^(1x)alkylene-Het,O-alkylene-N(R^(1x))₂, O-alkylene-CH(OR^(1y))CH₂N(R^(1x))₂,O-alkylene-Het, O-alkylene-OR^(1x), O-alkylene-NR^(1x)(═O)OR^(1x),NR^(1x)-alkylene-N(R^(1x))₂, NR^(1x)C(═O)R^(1x), NR^(1x)C(═O)N(R^(1x))₂,N(SO₂-alkyl)₂, NR^(1x)(SO₂-alkyl), SO₂R^(1x), SO₂N(R^(1x))₂, OSO₂CF₃,alkylenearyl, alkylene-Het, alkylene-OR^(1y), alkylene-N(R^(1x))₂,C(═O)N(R^(1x))₂, NHC(═O)alkylenearyl, unsubstituted or substitutedcycloalkyl, unsubstituted or substituted heteocycloalkyl,aryl-O-alkylene-N(R^(1x))₂, aryl-OC(═O)R^(1y),NHC(═O)alkylene-heterocycloalkyl, NHC(═O)alkyelne-Het,O-alkylene-O-alkylene-C(═O)OR^(1y), C(═O)alkylene-Het, orNHC(═O)haloalkyl,

wherein Het is a 5- or 6-membered heterocyclic ring containing at leastone heteroatom selected from the group consisting of oxygen, nitrogenand sulfur, wherein the 5- or 6-membered heterocyclic ring is saturated,partially unsaturated or fully unsaturated, and wherein Het isunsubstituted or substituted with alkyl or C(═O)OR^(1x),

wherein R^(1x) is independently hydrogen, unsubstituted or substitutedalkyl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted heterocycloalkyl, alkylene-N(R^(1x))₂, unsubstituted orsubstituted aryl, arylalkyl, alkylenearyl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted heteroarylalkyl, oralkyleneheteroaryl, or two R^(1a) groups are taken together to form a 5-or 6-membered ring, optionally containing at least one heteroatom,

wherein R^(1y) is hydrogen, unsubstituted or substituted alkyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, arylalkyl, heteroarylalkyl, alkylenearyl, andalkyleneheteroaryl;

m is 0, 1, 2, or 3;

each R² is independently halo, cyano, unsubstituted or substitutedalkyl, unsubstituted or substituted haloalkyl, unsubstituted orsubstituted alkoxy, or NR^(2x)R^(2y), wherein each R^(2x) and R^(2y) isindependently hydrogen, C(O)R^(2s) or C(O)OR^(2s), wherein R^(2s) isunsubstituted or substituted alkyl;

R³ is hydrogen or unsubstituted or substituted alkyl; and

R⁴ is cyano, CON(R^(4a))₂, SO₂-alkyl, halo, or haloalkyl, where eachR^(4a) is independently hydrogen, or unsubstituted or substituted alkyl.

In some embodiments of formula (J) where A is N, the compound is offormula (JA):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

In other embodiments of formula (J) where A is CH, the compound is offormula (JB):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

In some embodiments of formula (JA) or (JB),

each R¹ is independently halo, cyano, unsubstituted or substitutedalkyl, unsubstituted or substituted haloalkyl, unsubstituted orsubstituted alkoxy, hydroxy, unsubstituted or substituted cycloalkyl,—SO₂R^(1x), or —C(O)N(R^(1x))₂, wherein each R^(1′) is independentlyhydrogen or unsubstituted or substituted alkyl;

each R² is independently halo, cyano, unsubstituted or substitutedalkyl, unsubstituted or substituted haloalkyl, unsubstituted orsubstituted alkoxy, or N(R^(2x))₂, wherein each R^(2x) is independentlyhydrogen, C(O)R^(2s) or C(O)OR^(2s), wherein R^(2s) is unsubstituted orsubstituted alkyl; and

R³ and R⁴ are as defined for formula (J).

In another aspect, provided is a compound of formula (I):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein each of n, R¹, m, R², and R³ is as defined for formula (J).

In some embodiments of formula (I):

n is 0, 1, 2, or 3;

each R¹ is independently halo, cyano, unsubstituted or substitutedalkyl, unsubstituted or substituted haloalkyl, unsubstituted orsubstituted alkoxy, hydroxy, unsubstituted or substituted cycloalkyl,—SO₂R^(1r), or —C(O)NR^(1s)R^(1t), wherein each R^(1r), R^(1s) andR^(1t) is independently hydrogen or unsubstituted or substituted alkyl;

m is 0, 1, 2, or 3;

each R² is independently halo, cyano, unsubstituted or substitutedalkyl, unsubstituted or substituted haloalkyl, or unsubstituted orsubstituted alkoxy; and

R³ is hydrogen, or unsubstituted or substituted alkyl.

In some embodiments of formula (I), one or both of the followingproperties apply:

(i) n is 1, 2 or 3; and

(ii) m is 1, 2 or 3.

In other embodiments of formula (I) where n is 2 and m is 2, thecompound is of formula (IA-1):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein:

each R^(1a) and R^(1b) can be selected from the moieties defined for R¹of formula (I);

each R^(2a) and R^(2b) can be selected from the moieties defined for R²of formula (I); and

R³ is as defined for formula (I).

In certain embodiments of formula (IA-1),

each R^(1a) and R^(1b) is independently halo, cyano, unsubstituted orsubstituted alkyl, unsubstituted or substituted haloalkyl, unsubstitutedor substituted alkoxy, hydroxy, or unsubstituted or substitutedcycloalkyl;

each R^(2a) and R^(2b) is independently halo, cyano, unsubstituted orsubstituted alkyl, unsubstituted or substituted haloalkyl, orunsubstituted or substituted alkoxy; and

R³ is unsubstituted or substituted alkyl.

In other embodiments of formula (I) where n is 2 and m is 2, thecompound is of formula (IA-2):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein each of R^(1a), R^(1b), R^(2a), R^(2b) and R³ is as defined forformula (IA-1).

In other embodiments of formula (I) where n is 1 and m is 2, thecompound is of formula (IB-1):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein:

R^(1a) can be selected from the moieties defined for R¹ of formula (I);

each R^(2a) and R^(2b) can be selected from the moieties defined for R²of formula (I); and

R³ is as defined for formula (I).

In certain embodiments of formula (IB-1),

R^(1a) is halo, cyano, unsubstituted or substituted alkyl, orunsubstituted or substituted haloalkyl;

each R^(2a) and R^(2b) is independently hydrogen, halo or cyano; and

R³ is unsubstituted or substituted alkyl.

In yet other embodiments of formula (I) where n is 1 and m is 2, thecompound is of formula (IB-2):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein each of R^(1a), R^(2a), R^(2b) and R³ is as defined for formula(IB-1).

In yet other embodiments of formula (I) where n is 1 and m is 2, thecompound is of formula (IB-3):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein each of R^(1a), R^(2a), R^(2b) and R³ is as defined for formula(IB-1).

In yet other embodiments of formula (I) where n is 1 and m is 2, thecompound is of formula (IB-4):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein each of R^(1a), R^(2a), R^(2b) and R³ is as defined for formula(IB-1).

Provided are also compounds selected from Table 1, or a pharmaceuticallyacceptable salt, prodrug, or solvate thereof. In some embodiments, thecompound is selected from Compound No. 1-89, 95-99, 101-103, and106-110, or a pharmaceutically acceptable salt, prodrug, or solvatethereof. In other embodiments, the compound is selected from CompoundNo. 90-94, 100, 104, and 105, or a pharmaceutically acceptable salt,prodrug, or solvate thereof. In one embodiment, the compound is(S)-2,4-diamino-6-((1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinaltsazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile,or a pharmaceutically acceptable salt, prodrug, or solvate thereof. Inother embodiments, the compound is selected from Compound No. 111-122,124, 125, 127, 129-133, 135-138, 140, 141, 145, 146, 148-156, 159-168,175, 176, 178, 179, 181-186, 190, 192, 193, 194, 195-198, 205, 206, 142,187-189, 191, 199, 200-204 and 207, or a pharmaceutically acceptablesalt, prodrug, or solvate thereof.

Also provided is a pharmaceutical composition that includes a compoundof formula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4),or a pharmaceutically acceptable salt, prodrug, or solvate thereof,together with at least one pharmaceutically acceptable vehicle. Examplesof pharmaceutically acceptable vehicle may be selected from carriers,adjuvants, and excipients.

Also provided is a method of treating a subject, who has or is suspectedof having a disease or condition responsive or believed to be responsiveto the inhibition of PI3Kδ activity by administering to the subject acompound of formula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or(IB-4), or a pharmaceutically acceptable salt, prodrug, or solvatethereof. In some embodiments, the subject is a human.

Also provided is a method of inhibiting kinase activity of aphosphatidylinositol 3-kinase delta polypeptide by contacting thepolypeptide with a compound of formula (J), (I), (IA-1), (IA-2), (IB-1),(IB-2), (IB-3), or (IB-4), or a pharmaceutically acceptable salt,prodrug, or solvate thereof. Further provided is a method of inhibitingexcessive or destructive immune reactions, such as asthma, rheumatoidarthritis, multiple sclerosis, and lupus.

Also provided is a method of disrupting leukocyte function comprisingcontacting the leukocytes with an effective amount of a compound offormula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), ora pharmaceutically acceptable salt, prodrug, or solvate thereof.

Also provided is a method of inhibiting a growth or a proliferation ofcancer cells comprising contacting the cancer cells with an effectiveamount of a compound of formula (J), (I), (IA-1), (IA-2), (IB-1),(IB-2), (IB-3), or (IB-4), or a pharmaceutically acceptable salt,prodrug, or solvate thereof. Also provided is a method for increasingsensitivity of cancer cells to chemotherapy, comprising administering toa patient undergoing chemotherapy with a chemotherapeutic agent anamount a compound of formula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2),(IB-3), or (IB-4), or a pharmaceutically acceptable salt, prodrug, orsolvate thereof, sufficient to increase the sensitivity of cancer cellsto the chemotherapeutic agent. In some embodiments, the cancers cellsare of hematopoietic origin.

Also provided is a kit that includes a compound of formula (J), (I),(IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or a pharmaceuticallyacceptable salt, prodrug, or solvate thereof; and a label and/orinstructions for use of the compound in the treatment of a disease orcondition mediated by PI3Kδ activity.

Also provided are articles of manufacture that include a compound offormula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), ora pharmaceutically acceptable salt, prodrug, or solvate thereof; and acontainer. In one embodiment, the container may be a vial, jar, ampoule,preloaded syringe, or an intravenous bag.

DETAILED DESCRIPTION

The following description sets forth exemplary methods, parameters andthe like. It should be recognized, however, that such description is notintended as a limitation on the scope of the present disclosure but isinstead provided as a description of exemplary embodiments.

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”.

“Alkyl” refers to a monoradical unbranched or branched saturatedhydrocarbon chain. In some embodiments, alkyl as used herein, such as incompounds of formula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3),or (IB-4), has 1 to 20 carbon atoms (i.e., C₁₋₂₀ alkyl), 1 to 8 carbonatoms (i.e., C₁₋₈ alkyl), 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl), or 1to 4 carbon atoms (i.e., C₁₄ alkyl). Examples of alkyl groups includemethyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and3-methylpentyl. When an alkyl residue having a specific number ofcarbons is named, all geometric isomers having that number of carbonsmay be encompassed; thus, for example, “butyl” can include n-butyl,sec-butyl, isobutyl and t-butyl; “propyl” can include n-propyl andisopropyl.

“Cycloalkyl.” refers to a cyclic alkyl group. In some embodiments,cycloalkyl as used herein, such as in compounds of formula (J), (I),(IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), has from 3 to 20 ringcarbon atoms (i.e., C₃₋₂₀ cycloalkyl), or 3 to 12 ring carbon atoms(i.e., C₃₋₁₂ cycloalkyl), or 3 to 8 ring carbon atoms (i.e., C₃₋₈cycloalkyl). Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Heterocycloalkyl” refers to a cyclic alkyl group, with one or more ringheteroatoms independently selected from nitrogen, oxygen and sulfur. Insome embodiments, the heterocycloalkyl as used herein, such as incompounds of formula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3),or (IB-4), has 2 to 20 ring carbon atoms (i.e., C₂₋₂₀ heterocycloalkyl),2 to 12 ring carbon atoms (i.e., C₂₋₁₂ heterocycloalkyl), or 2 to 8 ringcarbon atoms (i.e., C₂₋₈ heterocycloalkyl); and 1 to 5 ring heteroatoms,1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ringheteroatoms, or 1 ring heteroatom independently selected from nitrogen,sulfur or oxygen. In one example, a heterocycloalkyl has 2 to 8 ringcarbon atoms, with 1 to 3 ring heteroatoms independently selected fromnitrogen, oxygen and sulfur. Examples of heterocycloalkyl groups mayinclude pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl,azetidinyl, and morpholinyl.

“Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groups mayinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

“Aryl” refers to an aromatic carbocyclic group having a single ring(e.g., phenyl), multiple rings (e.g., biphenyl), or multiple fused rings(e.g., naphthyl, fluorenyl, and anthryl). In certain embodiments, arylas used herein, such as in compounds of formula (J), (I), (IA-1),(IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), has 6 to 20 ring carbon atoms(i.e., C₆₋₂₀ aryl), or 6 to 12 carbon ring atoms (i.e., C₆₋₁₂ aryl).Aryl, however, does not encompass or overlap in any way with heteroaryl,separately defined below. In certain embodiments, if one or more arylgroups are fused with a heteroaryl ring, the resulting ring system isheteroaryl.

“Heteroaryl” refers to an aromatic group having a single ring, multiplerings, or multiple fused rings, with one or more ring heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, heteroaryl is an aromatic, monocyclic or bicyclic ringcontaining one or more heteroatoms independently selected from nitrogen,oxygen and sulfur with the remaining ring atoms being carbon. In certainembodiments, heteroaryl as used herein, such as in compounds of formula(J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), has 3 to 20ring carbon atoms (i.e., C₃₋₂₀ heteroaryl), 3 to 12 ring carbon atoms(i.e., C₃₋₁₂) heteroaryl), or 3 to 8 carbon ring atoms (i.e., C₃₋₈heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ringheteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom independentlyselected from nitrogen, oxygen, and sulfur. In one example, a heteroarylhas 3 to 8 ring carbon atoms, with 1 to 3 ring heteroatoms independentlyselected from nitrogen, oxygen and sulfur. Examples of heteroaryl groupsinclude pyridyl, pyridazinyl, pyrimidinyl, benzothiazolyl, andpyrazolyl. Heteroaryl does not encompass or overlap with aryl as definedabove.

The term “substituted”, as used herein, means that any one or morehydrogen atoms on the designated atom or group is replaced with a moietyother than hydrogen, provided that the designated atom's normal valenceis not exceeded.

“Substituted alkyl” refers to an alkyl group having one or moresubstituents including, for example, hydroxyl, haloalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, cyano, halo, carboxyl, and NR₂,where each R is independently hydrogen, alkyl, haloalkyl, alkylC(O)—,alkylOC(O)—, or H₂NC(O)—. In some embodiments, a substituted alkyl mayhave 1 to 5 substituents, 1 to 3 substituents, 1 to 2 substituents, or 1substituent.

“Substituted cycloalkyl” refers to a cycloalkyl group having one or moresubstituents including, for example, alkyl, haloalkyl, heterocycloalkyl,aryl, heteroaryl, alkoxy, cyano, halo, carboxyl, hydroxyl, and NR₂,where each R is independently hydrogen, haloalkyl, alkylC(O)—,alkylOC(O)—, or H₂NC(O)—. In some embodiments, a substituted cycloalkylmay have 1 to 5 substituents, 1 to 3 substituents, 1 to 2 substituents,or 1 substituent.

“Substituted heterocycloalkyl” refers to a heterocycloalkyl group havingone or more substituents including, for example, alkyl, haloalkyl,cycloalkyl, aryl, heteroaryl, alkoxy, cyano, halo, carboxyl, hydroxyl,and NR₂, where each R is independently hydrogen, alkyl, haloalkyl,alkylC(O)—, alkylOC(O)—, or H₂NC(O)—. In some embodiments, a substitutedheterocycloalkyl may have 1 to 5 substituents, 1 to 3 substituents, 1 to2 substituents, or 1 substituent. In certain embodiments, a substitutedheterocycloalkyl may contain 1, 2 or 3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

“Substituted aryl” refers to an aryl group having one or moresubstituents including, for example, halo, OR, NR₂, C(O)NR′₂, SO₂NR′₂,heterocycloalkyl, heteroaryl, alkoxy, amino, cyano, and carboxyl, whereeach R is independently hydrogen, alkyl, haloalkyl, alkylC(O)—,alkylOC(O)—, or H₂NC(O)— and each R′ is independently hydrogen, alkyl,haloalkyl. In some embodiments, a substituted aryl may have 1 to 5substituents, 1 to 3 substituents, 1 to 2 substituents, or 1substituent.

“Substituted heteroaryl” refers to a heteroaryl group having one or moresubstituents including, for example, alkyl, haloalkyl, halo, NR₂, OR,—C(O)OR, heterocycloalkyl, aryl, and cyano, where each R isindependently hydrogen, alkyl, haloalkyl, alkylC(O)—, alkylOC(O)—, orH₂NC(O)—. In some embodiments, a substituted heteroaryl may have 1 to 5substituents, 1 to 3 substituents, 1 to 2 substituents, or 1substituent. In certain embodiments, a substituted heteroaryl maycontain 1, 2 or 3 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

The term “halogen” or “halo” includes fluoro, chloro, bromo, and iodo,and the term “halogen” includes fluorine, chlorine, bromine, and iodine.“Haloalkyl” refers to an unbranched or branched alkyl group as definedabove, wherein one or more hydrogen atoms are replaced by a halogen. Forexample, where a residue is substituted with more than one halogen, itmay be referred to by using a prefix corresponding to the number ofhalogen moieties attached. For example, dihaloaryl, dihaloalkyl, andtrihaloaryl refer to aryl and alkyl substituted with two (“di”) or three(“tri”) halo groups, which may be, but are not necessarily, the samehalogen; thus, for example, 3,5-difluorophenyl, 3-chloro-5-fluorophenyl,4-chloro-3-fluorophenyl, and 3,5-difluoro-4-chlorophenyl is within thescope of dihaloaryl. Other examples of a haloalkyl group includedifluoromethyl (—CHF₂) and trifluoromethyl (—CF₃). It should beunderstood that trifluoromethyl (—CF₃) may also be referred to asperfluoromethyl.

PI3K Inhibitor Compounds

Provided herein are compounds that function as inhibitors of PI3Kisoforms, such as PI3Kδ. In one aspect, provided is a compound offormula (J):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein:

A is N or CH;

-   -   n is 0, 1, 2, or 3;    -   each R¹ is independently unsubstituted or substituted alkyl,        unsubstituted or substituted haloalkyl, unsubstituted or        substituted aryl, unsubstituted or substituted heteroaryl, halo,        cyano, NHC(═O)alkylene-N(R^(1x))₂, NO₂, ° R^(1x), OCF₃,        N(R^(1x))₂, OC(═O)R^(1x), C(═O)R^(1x), C(═O)OR^(1x),        aryl-OR^(1y), Het, NR^(1x)C(═O)alkylene-C(═O)OR^(1x),        aryl-O-alkylene-N(R^(1x))₂, aryl-O—C(═O)R^(1x),        alkylene-C(═O)OR^(1x), O-alkylene-C(═O)OR^(1x),        alkylene-O-alkylene-C(═O)OR^(1x), C(═O)NR^(1x)SO₂R^(1x),        alkylene-N(R^(1x))₂, alkenylene-N(R^(1x))₂,        C(═O)NR^(1x)-alkylene-OR^(1x), C(═O)NR^(1x)alkylene-Het,        O-alkylene-N(R^(1x))₂, O-alkylene-CH(OR^(1y))CH₂N(R^(1x))₂,        O-alkylene-Het, O-alkylene-OR^(1x),        O-alkylene-NR^(1x)C(═O)OR^(1x), NR^(1x)-alkylene-N(R^(1x))₂,        NR^(1x)C(═O)R^(1x), NR^(1x)C(═O)N(R^(1x))₂, N(SO₂-alkyl)₂,        NR^(1x)(SO₂-alkyl), SO₂R^(1x), SO₂N(R^(1x))₂, OSO₂CF₃,        alkylenearyl, alkylene-Het, alkylene-OR^(1y),        alkylene-N(R^(1x))₂, C(═O)N(R^(1x))₂, NHC(═O)alkylenearyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heteocycloalkyl, aryl-O-alkylene-N(R^(1x))₂,        aryl-OC(═O)R^(1y), NHC(═O)alkylene-heterocycloalkyl,        NHC(═O)alkyelne-Het, O-alkylene-O-alkylene-C(═O)OR¹Y,        C(═O)alkylene-Het, or NHC(═O)haloalkyl,

wherein Het is a 5- or 6-membered heterocyclic ring containing at leastone heteroatom selected from the group consisting of oxygen, nitrogenand sulfur, wherein the 5- or 6-membered heterocyclic ring is saturated,partially unsaturated or fully unsaturated, and wherein Het isunsubstituted or substituted with alkyl or C(═O)OR^(1x),

wherein R^(1x) is independently hydrogen, unsubstituted or substitutedalkyl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted heterocycloalkyl, alkylene-N(R^(1x))₂, unsubstituted orsubstituted aryl, arylalkyl, alkylenearyl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted heteroarylalkyl, oralkyleneheteroaryl, or two R^(1a) groups are taken together to form a 5-or 6-membered ring, optionally containing at least one heteroatom,

wherein R^(1y) is hydrogen, unsubstituted or substituted alkyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, arylalkyl, heteroarylalkyl, alkylenearyl, andalkyleneheteroaryl;

m is 0, 1, 2, or 3;

each R² is independently halo, cyano, unsubstituted or substitutedalkyl, unsubstituted or substituted haloalkyl, unsubstituted orsubstituted alkoxy, or NR^(2x)R^(2y), wherein each R^(2x) and R^(2y) isindependently hydrogen, C(O)R^(2s) or C(O)OR^(2s), wherein R^(2s) isunsubstituted or substituted alkyl;

R³ is hydrogen, unsubstituted or substituted alkyl, or unsubstituted orsubstituted haloalkyl; and

R⁴ is cyano, CON(R^(4a))₂, SO₂-alkyl, halo, or haloalkyl, where eachR^(4a) is independently hydrogen, or unsubstituted or substituted alkyl.

In some embodiments of formula (J),

A is N or CH;

n is 0, 1, 2, or 3;

each R¹ is independently halo, cyano, unsubstituted or substitutedalkyl, unsubstituted or substituted haloalkyl, unsubstituted orsubstituted alkoxy, hydroxy, unsubstituted or substituted cycloalkyl,SO₂R^(1r), or C(O)NR^(1s)R^(1t), wherein each R^(1r), R^(1s) and R^(1t)is independently hydrogen or unsubstituted or substituted alkyl;

m is 0, 1, 2, or 3;

each R² is independently halo, cyano, unsubstituted or substitutedalkyl, unsubstituted or substituted haloalkyl, or unsubstituted orsubstituted alkoxy;

R³ is hydrogen or unsubstituted or substituted alkyl; and

R⁴ is cyano, CON(R^(4a))₂, SO₂-alkyl, halo, or haloalkyl, where eachR^(4a) is independently hydrogen, or unsubstituted or substituted alkyl.

In other embodiments of formula (J),

A is N or CH;

n is 0, 1, 2, or 3;

each R¹ is independently halo, cyano, OR^(1x), C(═O)OR^(1x), SO₂R^(1x),or C(═O)N(R^(1x))₂, wherein R^(1x) is independently hydrogen, orunsubstituted or substituted alkyl;

m is 0, 1, 2, or 3;

each R² is independently halo, cyano, unsubstituted or substitutedalkyl, unsubstituted or substituted haloalkyl, or unsubstituted orsubstituted alkoxy;

R³ is hydrogen, unsubstituted or substituted alkyl, or unsubstituted orsubstituted haloalkyl; and

R⁴ is cyano, CON(R^(4a))₂, halo, or haloalkyl, where each R^(4a) isindependently hydrogen, or unsubstituted or substituted alkyl.

In some embodiments of formula (J), each R¹ is independently fluoro,chloro, cyano, methyl, CHF₂, CF₃, methoxy, or hydroxy. In otherembodiments of formula (J), each R¹ is independently halo, cyano,OR^(1x), C(═O)OR^(1x), SO₂R^(1x), or C(═O)N(R^(1x))₂, wherein R^(1x) isindependently hydrogen, or unsubstituted or substituted alkyl.

In certain embodiments of formula (J), n is 0, 1 or 2. In certainembodiments of formula (J), n is 1 or 2.

In some embodiments of formula (J), each R² is independently fluoro,chloro, iodo, cyano, methoxy, CHF₂, or CF₃. In other embodiments offormula (J), each R² is independently halo or substituted alkoxy. In oneembodiment, each R² is independently fluoro or —OCF₃.

In certain embodiments of formula (J), m is 1 or 2.

In some embodiments of formula (J), R³ is alkyl substituted with halo oralkoxy. In one embodiment, R³ is —CH₂CF₃ or —CH₂OCH₃. In otherembodiments of formula (J), R³ is unsubstituted alkyl. In oneembodiment, R³ is methyl, ethyl, propyl or butyl. In another embodiment,R³ is methyl or ethyl.

In some embodiments of formula (J), R⁴ is halo. In one embodiment, R⁴ ischloro.

In certain embodiments of formula (J),

n is 1, 2, or 3;

each R¹ is independently halo, cyano or unsubstituted or substitutedalkyl;

m is 1, 2, or 3;

each R² is independently halo or cyano; and

R³ is unsubstituted or substituted alkyl.

In certain embodiments of formula (J),

n is 1;

R¹ is halo;

m is 2;

each R² is independently halo;

R³ is unsubstituted or substituted alkyl.

In some embodiments of formula (J) where A is N, the compound is offormula (JA):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

In other embodiments of formula (J) where A is CH, the compound is offormula (JB):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

In some embodiments of formula (JA) or (JB),

each R¹ is independently halo, cyano, unsubstituted or substitutedalkyl, unsubstituted or substituted haloalkyl, unsubstituted orsubstituted alkoxy, hydroxy, unsubstituted or substituted cycloalkyl,—SO₂R^(1x), or —C(O)N(R^(1x))₂, wherein each R^(1x) is independentlyhydrogen or unsubstituted or substituted alkyl;

each R² is independently halo, cyano, unsubstituted or substitutedalkyl, unsubstituted or substituted haloalkyl, unsubstituted orsubstituted alkoxy, or N(R^(2x))₂, wherein each R^(2x) is independentlyhydrogen, C(O)R^(2s) or C(O)OR^(2s), wherein R^(2s) is unsubstituted orsubstituted alkyl; and

R³ and R⁴ are as defined for formula (J).

It is intended and understood that each and every variation of R¹ and R²may be combined with each and every variation of n, m, R³ and R⁴ asdescribed for formula (JA) or (JB), as if each and every combination isindividually described.

In some embodiments of formula (JA) or (JB), R³ is hydrogen. In otherembodiments, R³ is unsubstituted or substituted alkyl. In certainembodiments, R³ is methyl or ethyl. It is intended and understood thateach and every variation of R³ may be combined with each and everyvariation of n, R¹, m, R² and R⁴ as described for formula (JA) or (JB),as if each and every combination is individually described.

In some embodiments of formula (JA) or (JB), R⁴ is cyano, fluoro,chloro, CONH₂, or SO₂CH₃. In one embodiment, R⁴ is cyano. It is intendedand understood that each and every variation of R⁴ may be combined witheach and every variation of n, R¹, m, R² and R³ as described for formula(JA) or (JB), as if each and every combination is individuallydescribed.

In some embodiments of formula (J), (JA), or (JB), one or both of thefollowing properties apply:

(i) n is 1, 2 or 3; and

(ii) m is 1, 2 or 3.

It is intended and understood that each and every variation of n and mmay be combined with each and every variation of R¹, R², R³ and R⁴ asdescribed for formula (J), (JA), and (JB), as if each and everycombination is individually described.

The embodiments and variations described herein are suitable forcompounds of any formulae detailed herein, where applicable. Forexample, the embodiments and structures as described herein with respectto formula (J) are suitable for compounds of any formulae detailedherein, including (JA) and (JB) where applicable.

In another aspect, provided is a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein each of n, R¹, m,R², and R³ are as defined for formula (J).

In some embodiments of formula (I),

n is 0, 1, 2, or 3;

each R¹ is independently halo, cyano, unsubstituted or substitutedalkyl, unsubstituted or substituted haloalkyl, unsubstituted orsubstituted alkoxy, hydroxy, unsubstituted or substituted cycloalkyl,—SO₂R^(1r), or —C(O)NR^(1s)R^(1t), wherein each R^(1r), R^(1s) andR^(1t) is independently hydrogen or unsubstituted or substituted alkyl;

m is 0, 1, 2, or 3;

each R² is independently halo, cyano, unsubstituted or substitutedalkyl, unsubstituted or substituted haloalkyl, or unsubstituted orsubstituted alkoxy; and

R³ is hydrogen, or unsubstituted or substituted alkyl.

In some embodiments of formula (I), one or both of the followingproperties apply:

(i) n is 1, 2 or 3; and

(ii) m is 1, 2 or 3.

In one embodiment of formula (I), n is 0. In other embodiments, n is 1,2 or 3. In certain embodiments, n is 1 or 2. In one embodiment, n is 1.The R¹ moiety may be located on any position of the quinazolinone ring,as depicted below.

In another embodiment, n is 2. In embodiments where n is 2, both R¹ maybe the same or different. Two R¹ moieties may be located of any twopositions of the quinazolinone ring as depicted below. For example, twoR¹ moieties may be in para-, meta- or ortho-positions to each other.

In yet another embodiment, n is 3. In embodiments where n is 3, all R¹may be the same or different, or two R¹ may be the same and differentfrom the third R¹. Three R¹ moieties may be located on any threepositions of the quinazolinone ring as depicted below. For example, thefirst R¹ may be ortho to the second R¹, and the first R¹ may be para tothe third R¹.

In some embodiments of formula (I), each R¹ is independently halo,cyano, unsubstituted or substituted alkyl, unsubstituted or substitutedhaloalkyl, unsubstituted or substituted alkoxy, or hydroxy. In certainembodiments, each R¹ is independently halo, cyano, unsubstituted orsubstituted alkyl, or unsubstituted or substituted haloalkyl.

In some embodiments of formula (I), each R¹ is independently halo,cyano, unsubstituted or substituted C₁₋₆ alkyl, unsubstituted orsubstituted C₁₋₆ haloalkyl, unsubstituted or substituted C₁₋₆ alkoxy,hydroxy, or unsubstituted or substituted C₃₋₆ cycloalkyl. In certainembodiments, each R¹ is independently halo or unsubstituted orsubstituted C₁₋₆ alkyl.

In certain embodiments of formula (I), each R¹ is independently fluoro,chloro, cyano, methyl, CHF₂, CF₃, methoxy, hydroxy, CONH₂, SO₂CH₃, orcyclopropyl. In one embodiment, each R¹ is independently fluoro, chloro,cyano, methyl, CHF₂, CF₃, methoxy, or hydroxy. In another embodiment,each R¹ is independently fluoro, chloro, cyano or methyl.

In some embodiments of formula (I) where n is 1, R¹ is halo, cyano,unsubstituted or substituted alkyl, unsubstituted or substitutedhaloalkyl, unsubstituted or substituted alkoxy, hydroxy, —SO₂R^(1r), or—C(O)NR^(1s)R^(1t), or unsubstituted or substituted cycloalkyl. Incertain embodiments where n is 1, R¹ is fluoro, chloro, cyano, methyl,ethyl, CHF₂, CF₃, methoxy, hydroxy, CONH₂, SO₂CH₃, or cyclopropyl. Inone embodiment where n is 1, R¹ is fluoro, chloro, hydroxy, methyl,cyano, CHF₂, CF₃, or methoxy. In another embodiment where n is 1, R¹ isfluoro, chloro, or cyano. It should be understood that the R¹ moiety maybe located on any position of the quinazolinone ring.

In other embodiments of formula (I) where n is 2, both R¹ areindependently halo, which may the same (e.g., both R¹ are fluoro) orwhich may be different (e.g., one R¹ is fluoro and the other R¹ ischloro). In other embodiments where n is 2, one R¹ is halo and the otherR¹ is unsubstituted alkyl. In certain embodiments where n is 2, both R¹are chloro or both R¹ are fluoro. In yet other embodiments where n is 2,one R¹ is chloro and the other R¹ is fluoro; one R¹ is chloro and theother R¹ is methyl; or one R¹ is fluoro and the other R¹ is methyl. Itshould be understood that the two R¹ moieties may be located of any twopositions of the quinazolinone ring as depicted below.

In some embodiments, the moiety

of formula (I) is:

In certain embodiments, the moiety

of formula (I) is:

It is intended and understood that each and every variation of n and R¹may be combined with each and every variation of m, R² and R³ asdescribed for formula (I), as if each and every combination isindividually described.

In some embodiments of formula (I), m is 0. In other embodiments, m is1, 2 or 3. In yet other embodiments, m is 1 or 2. In one embodiment, mis 1. The R² moiety may be located on any position of the phenyl ring,as depicted below.

In another embodiment, m is 2. In embodiments where m is 2, both R² maybe the same or different. The two R² moieties may be located on any twopositions of the phenyl ring, as depicted below.

In yet another embodiment, m is 3. In embodiments where m is 3, all R²may be the same or different, or two R² may be the same and differentfrom the third R². The three R² moieties may be located on any threepositions of the phenyl ring, as depicted below.

In some embodiments of formula (I), each R² is independently halo,cyano, unsubstituted or substituted C₁₋₆ alkyl, unsubstituted orsubstituted C₁₋₆ haloalkyl, or unsubstituted or substituted C₁₋₆ alkoxy.In certain embodiments, each R² is independently halo or cyano.

In certain embodiments of formula (I), each R² is independently fluoro,chloro, iodo, cyano, —NHC(O)NHCH₂CH₃, methoxy, CHF₂, or CF₃. In oneembodiment, each R² is independently fluoro, chloro, iodo, cyano,methoxy, CHF₂, or CF₃. In another embodiment, each R² is independentlyfluoro, chloro, or cyano.

In some embodiments of formula (I), m is 1 or 2. In some embodiments offormula (I) where m is 1, R² is halo, cyano, or haloalkyl. In certainembodiments where m is 1, R² is fluoro, chloro, cyano, CHF₂, or CF₃. Inone embodiment where m is 1, R² is fluoro, chloro, or cyano. It shouldbe understood that the R² moiety may be located on any position of thephenyl ring.

In some embodiments of formula (I) where m is 2, both R² areindependently halo, which may the same (e.g., both R² are fluoro) orwhich may be different (e.g., one R² is fluoro and the other R² ischloro). In other embodiments where m is 2, both R² are independentlyunsubstituted or substituted alkyl, which may the same (e.g., both R²are methyl) or which may be different (e.g., one R² is methyl and theother R² is ethyl). In other embodiments where m is 2, both R² areindependently unsubstituted or substituted haloalkyl, which may the same(e.g., both R² are CF₃) or which may be different (e.g., one R² is CF₃and the other R² is CHF₂). In yet other embodiments where m is 2, bothR² are independently unsubstituted or substituted alkoxy, which may thesame (e.g., both R² are methoxy) or which may be different (e.g., one R²is methoxy and the other R¹ is ethoxy). In other embodiments where m is2, one R² is halo and the other R² is cyano, one R² is halo and theother R² is unsubstituted or substituted haloalkyl, one R² is halo andthe other R² is unsubstituted or substituted alkyl, one R² is halo andthe other R² is unsubstituted or substituted alkoxy, or one R² is cyanoand the other R² is unsubstituted or substituted haloalkyl.

In certain embodiments of formula (I) where m is 2, both R² are fluoro,both R² are chloro, or both R² are methoxy. In yet other embodimentswhere m is 2, one R² is fluoro and the other R² is chloro, one R² isfluoro and the other R² is cyano, one R² is chloro and the other R² iscyano, one R² is fluoro and the other R² is CF₃, one R² is fluoro andthe other R² is CHF₂, one R² is chloro and the other R² is CF₃, one R²is chloro and the other R² is CHF₂, one R² is cyano and the other R² isCF₃, or one R² is cyano and the other R² is CHF₂. It should beunderstood that the two R² moieties may be located on any two positionsof the phenyl ring.

In yet other embodiments of formula (I) where m is 3, one or two of R²are independently halo, which may the same (e.g., two R² are fluoro) orwhich may be different (e.g., one R² is fluoro and another R² ischloro), the third R² is unsubstituted or substituted alkoxy (e.g.,third R² is methoxy). In another embodiment where m is 3, one R² isalkyl, another R² is alkoxy, and the third R² is halo. It should beunderstood that the three R² moieties may be located on any threepositions of the phenyl ring.

In some embodiments, the moiety

of formula (I) is:

In some embodiments, the moiety

of formula (I) is:

It is intended and understood that each and every variation of m and R²may be combined with each and every variation of n, R¹ and R³ asdescribed for formula (I), as if each and every combination isindividually described.

In some embodiments of formula (I), R³ is hydrogen, or unsubstituted orsubstituted C₁₋₆ alkyl. In one embodiment, R³ is hydrogen. In anotherembodiment, R³ is methyl or ethyl. It is intended and understood thateach and every variation of R³ may be combined with each and everyvariation of n, R¹, m and R² as described for formula (I), as if eachand every combination is individually described.

In some embodiments of formula (I),

n is 1, 2, or 3;

each R¹ is independently halo, cyano, or unsubstituted or substitutedalkyl;

m is 1, 2, or 3;

each R² is independently halo or cyano; and

R³ is unsubstituted alkyl.

In one embodiment of formula (I),

n is 1;

R¹ is halo;

m is 2;

each R² is independently halo; and

R³ is unsubstituted alkyl.

In some embodiments of formula (I) where n is 2 and m is 2, the compoundis of formula (IA-1):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein:

each R^(1a) and R^(1b) can be selected from the moieties defined for R¹of formula (I);

each R^(2a) and R^(2b) can be selected from the moieties defined for R²of formula (I); and

R³ is as defined for formula (I).

In certain embodiments of formula (IA-1),

each R^(1a), R^(1b) is independently halo, cyano, unsubstituted orsubstituted alkyl, unsubstituted or substituted haloalkyl, unsubstitutedor substituted alkoxy, hydroxy, or unsubstituted or substitutedcycloalkyl;

each R^(2a) and R^(2b) is independently halo, cyano, unsubstituted orsubstituted alkyl, unsubstituted or substituted haloalkyl, orunsubstituted or substituted alkoxy; and

R³ is unsubstituted or substituted alkyl.

In one embodiment of formula (IA-1),

each R^(1a) and R^(1b) is independently hydrogen, halo, cyano, orunsubstituted or substituted alkyl; and

each R^(2a) and R^(2b) is independently hydrogen, halo, or cyano.

In other embodiments of formula (I) where n is 2 and m is 2, thecompound is of formula (IA-2):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein:

each R^(1a) and R^(1b) can be selected from the moieties defined for R¹of formula (I);

each R^(2a) and R^(2b) can be selected from the moieties defined for R²of formula (I); and

R³ is as defined for formula (I).

In certain embodiments of formula (IA-1) or (IA-2),

each R^(1a) and R^(1b) is independently halo, cyano, unsubstituted orsubstituted alkyl, unsubstituted or substituted haloalkyl, unsubstitutedor substituted alkoxy, hydroxy, or unsubstituted or substitutedcycloalkyl;

each R^(2a) and R^(2b) is independently halo, cyano, unsubstituted orsubstituted alkyl, unsubstituted or substituted haloalkyl, orunsubstituted or substituted alkoxy; and

R³ is unsubstituted or substituted alkyl.

In some embodiments of formula (IA-1) or (IA-2), each R^(1a) and R^(1b)is independently halo, cyano, unsubstituted or substituted C₁₋₆ alkyl,unsubstituted or substituted C₁₋₆ haloalkyl, unsubstituted orsubstituted C₁₋₆ alkoxy, hydroxy, unsubstituted or substituted C₃₋₆cycloalkyl, —SO₂R^(1r), or —C(O)NR^(1s)R^(1t), wherein each R^(1r),R^(1s) and R^(1t) is independently hydrogen or unsubstituted orsubstituted C₁₋₆ alkyl. In certain embodiments, each R^(1a) and R^(1b)is independently halo, cyano, or unsubstituted alkyl. In one embodiment,each R^(1a) and R^(1b) is independently fluoro, chloro, cyano, methyl,CF₃, or CHF₂. In another embodiment, each R^(1a) and R^(1b) isindependently fluoro, chloro, cyano, or methyl. It is intended andunderstood that each and every variation of R^(1a) and R^(1b) may becombined with each and every variation of R^(2a), R^(2b), and R³ asdescribed for formula (IA-1) or (IA-2), as if each and every combinationis individually described.

In some embodiments of formula (IA-1) or (IA-2), each R^(2a) and R^(2b)is independently halo, cyano, unsubstituted or substituted C₁₋₆ alkyl,unsubstituted or substituted C₁₋₆ haloalkyl, or unsubstituted orsubstituted C₁₋₆ alkoxy. In certain embodiments, each R^(2a) and R^(2b)is independently halo, cyano, or unsubstituted C₁₋₆ alkyl. In oneembodiment, each R^(2a) and R^(2b) is independently fluoro, chloro,cyano, methyl, CF₃, or CHF₂. In another embodiment, each R^(2a) andR^(2b) is independently fluoro, chloro, or cyano. It is intended andunderstood that each and every variation of R^(2a) and R^(2b) may becombined with each and every variation of R^(1a), R^(1b), and R³ asdescribed for formula (IA-1) or (IA-2), as if each and every combinationis individually described.

In some embodiments, R³ is unsubstituted C₁₋₆ alkyl. In one embodiment,R³ is methyl. In another embodiment, R³ is ethyl. It is intended andunderstood that each and every variation of R³ may be combined with eachand every variation of R^(1a), R^(1b), R^(2a) and R^(2b) as describedfor formula (IA-1) or (IA-2), as if each and every combination isindividually described.

In other embodiments of formula (I) where n is 1 and m is 2, thecompound is of formula (IB-1):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein:

R^(1a) can be selected from the moieties defined for R¹ of formula (I);

each R^(2a) and R^(2b) can be selected from the moieties defined for R²of formula (I); and

R³ is as defined for formula (I).

In some embodiments of formula (IB-1),

R^(1a) is halo, cyano, unsubstituted or substituted alkyl, or haloalkyl;

each R^(2a) and R^(2b) is independently hydrogen, halo or cyano; and

R³ is unsubstituted or substituted alkyl.

In yet other embodiments of formula (I) where n is 1 and m is 2, thecompound is of formula (IB-2):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein each of R^(1a), R^(2a), R^(2b) and R³ is as defined for formula(IB-1).

In yet other embodiments of formula (I) where n is 1 and m is 2, thecompound is of formula (IB-3):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein each of R^(1a), R^(2a), R^(2b) and R³ is as defined for formula(IB-1).

In yet other embodiments of formula (I) where n is 1 and m is 2, thecompound is of formula (IB-4):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein each of R^(1a), R^(2a), R^(2b) and R³ is as defined for formula(IB-1).

In certain embodiments of formula (IB-4),

R^(1a) is halo, cyano, unsubstituted or substituted alkyl, or haloalkyl;

each R^(2a) and R^(2b) is independently hydrogen, halo or cyano; and

In certain embodiments of formula (IB-1), (IB-2), (IB-3), and (IB-4),

R^(1a) is halo, cyano, unsubstituted or substituted alkyl, orunsubstituted or substituted haloalkyl;

each R^(2a) and R^(2b) is independently hydrogen, halo or cyano; and

R³ is unsubstituted or substituted alkyl.

In some embodiments of formula (IB-1), (IB-2), (IB-3), and (IB-4),R^(1a) is fluoro or chloro. In one embodiment, R^(1a) is fluoro. Inanother embodiment, R^(1a) is chloro.

In other embodiments formula (IB-1), (IB-2), (IB-3), and (IB-4), eachR^(2a) and R^(2b) is independently fluoro, chloro, or cyano. In oneembodiment, both R^(2a) and R^(2b) are fluoro. In another embodiment,both R^(2a) and R^(2b) are chloro. In another embodiment, R^(2a) ischloro and R^(2b) is fluoro. In yet another embodiment, R^(2a) is fluoroand R^(2b) is chloro.

In yet other embodiments formula (IB-1), (IB-2), (IB-3), and (IB-4), R³is methyl or ethyl. In one embodiment, R³ is methyl. In anotherembodiment, R³ is ethyl.

It should be understood that the embodiments and structures as describedherein with respect to formula (I) are suitable for compounds of anyformulae detailed herein, including (IA-1), (IA-2), (IB-1), (IB-2),(IB-3), and (IB-4) where applicable.

For compounds of the invention, including the compounds of formula (J),(I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or apharmaceutically acceptable salt thereof, bearing one or more chiralcenters, each unique stereoisomer has a compound number bearing a suffix“a”, “b”, etc. As an example, Compound 1 bearing one chiral center canbe resolved into its individual enantiomers 1a and 1b.

In any one of the foregoing embodiments, the compound of formula (J),(I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or apharmaceutically acceptable salt thereof, is the (S)-enantiomer. Inother aspects, in any one of the foregoing embodiments, the compound offormula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), ora pharmaceutically acceptable salt thereof, is the (R)-enantiomer.

A composition containing a mixture of enantiomers of the compound offormula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), ora pharmaceutically acceptable salt thereof, is also provided herein. Insome embodiments, the composition contains the (S)-enantiomer of thecompound and is substantially free of its corresponding (R)-enantiomer.In certain embodiments, a composition substantially free of the(R)-enantiomer has less than or about 40%, 35%, 30%, 25%, 20%, 15%, 10%,5%, 1%, 0.05%, or 0.01% of the (R)-enantiomer. In other embodiments, thecomposition containing the (S)-enantiomer of a compound of formula (J),(I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or apharmaceutically acceptable salt thereof, predominates over itscorresponding (R)-enantiomer by a molar ratio of at least or about 9:1,at least or about 19:1, at least or about 40:1, at least or about 80:1,at least or about 160:1, or at least or about 320:1.

The composition containing a compound of formula (J), (I), (IA-1),(IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or a pharmaceuticallyacceptable salt thereof, may also contain the compound in enantiomericexcess (e.e.). For instance, a compound with 95% (S)-isomer and 5%(R)-isomer will have an e.e. of 90%. In some embodiments, the compoundhas an e.e. of at least or about 60%, 75%, 80%, 85%, 90%, 95%, 98% or99%. In some of the foregoing embodiments, the compound isenantiomerically-enriched in the (S)-isomer of compound of formula (J),(I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4).

Provided is also a composition comprising a mixture of the(S)-enantiomer and the (R)-enantiomer of a compound of formula (J), (I),(IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or a pharmaceuticallyacceptable salt thereof. In one embodiment, the mixture is a racemicmixture. In other embodiments, the composition comprises the(S)-enantiomer of a compound of formula (J), (I), (IA-1), (IA-2),(IB-1), (IB-2), (IB-3), or (IB-4), or a pharmaceutically acceptable saltthereof, wherein the (S)-enantiomer of the compound is present in excessof over the corresponding the (R)-enantiomer of the compound, or apharmaceutically acceptable salt thereof.

In certain embodiments, the compound of formula (J), (I), (IA-1),(IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or a pharmaceuticallyacceptable salt thereof, is a diastereomer. As an example, Compound 164is a diastereomer that can be resolved into its individual stereoisomersas depicted below.

In any one of the foregoing embodiments, the compound of formula (J),(I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or apharmaceutically acceptable salt thereof, is an atropisomer. Acomposition containing a mixture of atropisomers of the compound offormula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), ora pharmaceutically acceptable salt thereof, is also provided herein.“Atropisomers” refers to conformational stereoisomers which occur whenrotation about a single bond in the molecule is prevented, or greatlyslowed, as a result of steric interactions with other parts of themolecule and the substituents at both ends of the single bond areasymmetrical, i.e., they do not require a stereocenter. Where therotational barrier about the single bond is high enough, andinterconversion between conformations is slow enough, separation andisolation of the isomeric species may be permitted. Atropisomers areenantiomers without a single asymmetric atom. As an example, Compound142 can be resolved into its individual atropisomers as depicted below.

Representative compounds of the invention are listed in Table 1 below inits non-isomeric form. The compounds in Table 1 are named usingChemBioDraw Ultra 12.0 and it should be understood that other names maybe used to identify compounds of the same structure. Other compounds orradicals may be named with common names, or systematic or non-systematicnames. The compounds may also be named using other nomenclature systemsand symbols that are commonly recognized in the art of chemistryincluding, for example, Chemical Abstract Service (CAS) andInternational Union of Pure and Applied Chemistry (IUPAC). The namingand numbering of the compounds of the present disclosure is illustratedwith representative compounds of formula (J), (I), (IA-1), (IA-2),(IB-1), (IB-2), (IB-3), or (IB-4) shown in Table 1 below. The compoundsprovided in Table 1 may be a single enantiomer (e.g., (S)-enantiomer,(R)-enantiomer), or the compounds may be present in a composition havingan enantiomeric mixture.

TABLE 1 Representative Compounds # Structure Name 1.

2,4-diamino-6-((1-(5- chloro-3-(3,5- difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 2.

2,4-diamino-6-((1-(5- hydroxy-4-oxo-3-phenyl- 3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine- 5-carbonitrile a: (S)-enantiomer b:(R)-enantiomer 3.

2,4-diamino-6-((1-(8- methyl-4-oxo-3-phenyl- 3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine- 5-carbonitrile a: (S)-enantiomer b:(R)-enantiomer 4.

2,4-diamino-6-((1-(5- chloro-8-methyl-4-oxo-3- phenyl-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 5.

2,4-diamino-6-((1-(5- chloro-3-(3- chlorophenyl)-8-methyl- 4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 6.

2,4-diamino-6-((1-(3-(3- chlorophenyl)-8-methyl- 4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 7.

2-(1-((2,6-diamino-5- cyanopyrimidin-4- yl)amino)ethyl)-4-oxo-3-phenyl-3,4- dihydroquinazoline-5- carbonitrile a: (S)-enantiomerb:(R)-enantiomer 8.

2,4-diamino-6-((1-(5- chloro-3-(3- chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 9.

2,4-diamino-6-((1-(6- fluoro-4-oxo-3-phenyl- 3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine- 5-carbonitrile a: (S)-enantiomer b:(R)-enantiomer 10.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-5- fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 11.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-6- fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 12.

2,4-diamino-6-((1-(5- chloro-3-(3- cyanophenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 13.

2,4-diamino-6-((1-(3-(3- cyanophenyl)-6-fluoro-4- oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 14.

2,4-diamino-6-((1-(3-(3- chlorophenyl)-6-fluoro- 4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 15.

2,4-diamino-6-((1-(5- chloro-3-(3,5- difluorophenyl)-8-fluoro-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 16.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-8- fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 17.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-8- fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 18.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-5- methyl-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 19.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-5- methyl-4-oxo-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 20.

2,4-diamino-6-((1-(5- chloro-3-(3-cyano-5- fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 21.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-5,8- difluoro-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 22.

2,4-diamino-6-((1-(8- chloro-4-oxo-3-phenyl- 3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine- 5-carbonitrile a: (S)-enantiomer b:(R)-enantiomer 23.

2,4-diamino-6-((1-(5- methyl-4-oxo-3-phenyl- 3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine- 5-carbonitrile a: (S)-enantiomer b:(R)-enantiomer 24.

2,4-diamino-6-((1-(3-(3- cyano-5-fluorophenyl)-5- methyl-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 25.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-8- fluoro-5 methyl-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 26.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-6- fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 27.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-5,8- difluoro-4-oxo-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 28.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-4- oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 29.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-5,6- difluoro-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 30.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-5,6- difluoro-4-oxo-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 31.

2,4-diamino-6-((1-(3-(3- cyano-5-fluorophenyl)-8- fluoro-5-methyl-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 32.

2,4-diamino-6-((1-(3-(3- cyano-5-fluorophenyl)-5- fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 33.

2,4-diamino-6-((1-(5- fluoro-3-(3-fluoro-5- (trifluoromethyl)phenyl)-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 34.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-4- oxo-8-(trifluoromethyl)-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 35.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-5- fluoro-8-methyl-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 36.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-4- oxo-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 37.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-5- fluoro-8-methyl-4-oxo-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 38.

2,4-diamino-6-((1-(3-(3- cyanophenyl)-5-fluoro-4- oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 39.

2,4-diamino-6-((1-(8- methyl-4-oxo-3-(3- (trifluoromethyl)phenyl)-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 40.

2,4-diamino-6-((1-(5- fluoro-4-oxo-3-(3- (trifluoromethyl)phenyl)-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 41.

2,4-diamino-6-((1-(5- chloro-3-(3,5- dichlorophenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 42.

2,4-diamino-6-((1-(3- (3,5-dichlorophenyl)-5- fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 43.

2,4-diamino-6-((1-(5- chloro-3-(3-chloro-5- fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 44.

2,4-diamino-6-((1-(3-(3- chloro-5-fluorophenyl)- 5-fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 45.

2,4-diamino-6-((1-(5- chloro-3-(3-fluoro-5- (trifluoromethyl)phenyl)-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 46.

2,4-diamino-6-((1-(5- fluoro-4-oxo-3-(3- (trifluoromethyl)phenyl)-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 47.

2,4-diamino-6-((1-(5- chloro-4-oxo-3-(3- (trifluoromethyl)phenyl)-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 48.

2,4-diamino-6-((1-(5- chloro-3-(3-cyano-5- fluorophenyl)-8-fluoro-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrilea: (S)-enantiomer b: (R)-enantiomer 49.

2,4-diamino-6-((1-(5- chloro-4-oxo-3-phenyl- 3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine- 5-carbonitrile a: (S)-enantiomer b:(R)-enantitiomer 50.

2,4-diamino-6-((1-(5,8- dichloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 51.

2,4-diamino-6-((1-(5- chloro-3-(3,5- dimethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 52.

2,4-diamino-6-((1-(5- (difluoromethyl)-3-(3,5- difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 53.

2,4-diamino-6-((1-(5- (difluoromethyl)-3-(3,5- difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 54.

2,4-diamino-6-((1-(3-(3- (difluoromethyl)-5- fluorophenyl)-5-fluoro-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrilea: (S)-enantiomer b: (R)-enantiomer 55.

2,4-diamino-6-((1-(5- chloro-3-(3- (difluoromethyl)-5-fluorophenyl)-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 56.

2,4-diamino-6-((1-(8- (difluoromethyl)-4-oxo- 3-phenyl-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 57.

2,4-diamino-6-((1-(8- (difluoromethyl)-3-(3,5- difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 58.

2,4-diamino-6-((1-(8- fluoro-4-oxo-3-phenyl- 3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine- 5-carbonitrile a: (S)-enantiomer b:(R)-enantiomer 59.

2,4-diamino-6-((1-(5,8- difluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 60.

2,4-diamino-6-((1-(8- fluoro-5-methyl-4-oxo-3- phenyl-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 61.

2,4-diamino-6-((1-(5- fluoro-8-methyl-4-oxo-3- phenyl-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 62.

2,4-diamino-6-((1-(5- (difluoromethyl)-4-oxo- 3-phenyl-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 63.

2,4-diamino-6-((1-(3-(3- cyanophenyl)-5- (difluoromethyl)-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 64.

2,4-diamino-6-((1-(3-(3- cyanophenyl)-8-fluoro-5- methyl-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 65.

2,4-diamino-6-((1-(3-(3- (difluoromethyl)-5- fluorophenyl)-5-fluoro-4-oxo-3,4- dihydroquinazolin-2- yl)propyl)amino)pyrimidine- 5-carbonitrilea: (S)-enantiomer b: (R)-enantiomer 66.

2,4-diamino-6-((1-(5- chloro-3-(3- (difluoromethyl)-5-fluorophenyl)-4-oxo-3,4- dihydroquinazolin-2-yl)propyl)amino)pyrimidine- 5-carbonitrile a: (S)-enantiomer b:(R)-enantiomer 67.

2,4-diamino-6-((1-(8- chloro-3-(3,5- difluorophenyl)-5-fluoro-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 68.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-8- methoxy-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 69.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-6,8- difluoro-4-oxo-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 70.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-6,8- difluoro-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 71.

2,4-diamino-6-((1-(8- chloro-3-(3,5- difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 72.

2,4-diamino-6-((1-(8- chloro-3-(3,5- difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 73.

2,4-diamino-6-((1-(5- chloro-3-(3,5- difluorophenyl)-8-methyl-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 74.

2,4-diamino-6-((1-(5,8- dichloro-3-(3,5- difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 75.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-8- methyl-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 76.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-8- methyl-4-oxo-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 77.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-5- fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 78.

2,4-diamino-6-((1-(5- chloro-3-(3,5- difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 79.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-6,7- difluoro-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 80.

2,4-diamino-6-(((3-(3,5- difluorophenyl)-6,7- difluoro-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)amino)pyrimidine- 5-carbonitrile 81.

2,4-diamino-6-((1-(5- fluoro-4-oxo-3-phenyl- 3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine- 5-carbonitrile a: (S)-enantiomer b:(R)-enantiomer 82.

2,4-diamino-6-((1-(3-(3- cyanophenyl)-5-fluoro-8- methyl-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 83.

2,4-diamino-6-((1-(3-(3- cyano-5-fluorophenyl)-5- fluoro-8-methyl-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 84.

2,4-diamino-6-(((8- chloro-3-(3- cyanophenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)amino)pyrimidine- 5-carbonitrile 85.

2,4-diamino-6-((1-(6- chloro-3-(3,5- difluorophenyl)-5-fluoro-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 86.

2,4-diamino-6-((1-(6- chloro-3-(3,5- difluorophenyl)-5-fluoro-4-oxo-3,4- dihydroquinazolin-2- yl)propyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 87.

5-(5-chloro-2-(1-((2,6- diamino-5- cyanopyrimidin-4- yl)amino)ethyl)-4-oxoquinazolin-3(4H)- yl)isophthalonitrile a: (S)-enantiomer b:(R)-enantiomer 88.

2,4-diamino-6-((1-(3- (3,5- bis(trifluoromethyl)phen-yl)-5-fluoro-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 89.

2,4-diamino-6-((1-(8- chloro-3-(3,5- difluorophenyl)-6-fluoro-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 90.

2,4-diamino-6-(1-(5- chloro-3-(3,5- difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)ethylamino)pyrimidine- 5-carboxamide a:(S)-enantiomer b: (R)-enantiomer 91.

2-(1-((2,6-diamino-5- cyanopyrimidin-4- yl)amino)ethyl)-3-(3,5-difluorophenyl)-4-oxo- 3,4-dihydroquinazoline- 5-carboxamide a:(S)-enantiomer b: (R)-enantiomer 92.

2-(1-((2,6-diamino-5- cyanopyrimidin-4- yl)amino)ethyl)-4-oxo-3-phenyl-3,4- dihydroquinazoline-5- carboxamide a: (S)-enantiomer b:(R)-enantiomer 93.

2,4-diamino-6-(1-(5- chloro-3-(3- (difluoromethyl)-5-fluorophenyl)-4-oxo-3,4- dihydroquinazolin-2- yl)ethylamino)pyrimidine-5-carboxamide a: (S)-enantiomer b: (R)-enantiomer 94.

5-chloro-2-(1-(2,6- diamino-5- (methylsulfonyl)pyrimidin-4-ylamino)ethyl)-3- (3,5- difluorophenyl)quinazolin- 4(3H)-one a:(S)-enantiomer b: (R)-enantiomer 95.

2,4-diamino-6-(1-(5- (methylsulfonyl)-4-oxo- 3-phenyl-3,4-dihydroquinazolin-2- yl)ethylamino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 96.

2,4-diamino-6-(1-(3-(3,5- difluorophenyl)-5- (methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2- yl)ethylamino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 97.

2,4-diamino-6-(1-(3-(3- (difluoromethyl)phenyl)- 5-fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)ethylamino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 98.

2,4-diamino-6-(1-(3-(3- (difluoromethyl)-5- fluorophenyl)-5-(methylsulfonyl)-4-oxo- 3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine- 5-carbonitrile a: (S)-enantiomer b:(R)-enantiomer 99.

2,4-diamino-6-(1-(5- (difluoromethyl)-3-(3- (difluoromethyl)-5-fluorophenyl)-4-oxo-3,4- dihydroquinazolin-2- yl)ethylamino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 100.

2,4-diamino-6-(1-(5- chloro-3-(3- (difluoromethyl)phenyl)- 4-oxo-3,4-dihydroquinazolin-2- yl)ethylamino)pyrimidine- 5-carboxamide a:(S)-enantiomer b: (R)-enantiomer 101.

2-(1-((2,6-diamino-5- cyanopyrimidin-4- yl)amino)ethyl)-3-(3,5-difluorophenyl)-4-oxo- 3,4-dihydroquinazoline- 8-carbonitrile- a:(S)-enantiomer b: (R)-enantiomer 102.

2,4-diamino-6-((1-(8- chloro-3-(3,5- difluorophenyl)-5-fluoro-4-oxo-3,4- dihydroquinazolin-2- yl)propyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 103.

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-8- ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 104.

5-chloro-2-(1-((2,6- diamino-5- chloropyrimidin-4- yl)amino)ethyl)-3-phenylquinazolin-4(3H)- one a: (S)-enantiomer b: (R)-enantiomer 105.

2-(1-((2,6-diamino-5- chloropyrimidin-4- yl)amino)propyl)-3-(3,5-difluorophenyl)-5- fluoroquinazolin-4(3H)- one a: (S)-enantiomer b:(R)-enantiomer 106.

2,4-diamino-6-(1-(5- chloro-3-(3- (difluoromethyl)phenyl)- 4-oxo-3,4-dihydroquinazolin-2- yl)ethylamino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 107.

2,4-diamino-6-(1-(5- chloro-3-(3- isopropylphenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)ethylamino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 108.

2,4-diamino-6-(1-(5- chloro-3-(3- fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)ethylamino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 109.

2,4-diamino-6-(1-(5- chloro-3-(3-methoxy-2- methylphenyl)-4-oxo-3,4-dihydroquinazolin-2- yl)ethylamino)pyrimidine- 5-carbonitrile a:(S)-enantiomer a-1 and a-2: atropisomers b: (R)-enantiomer b-1 and b-2:atropisomers 110.

2,4-diamino-6-(1-(5- chloro-3-(5 fluoro-3- methoxy-2-methylphenyl)-4-oxo- 3,4-dihydroquinazolin-2- yl)ethylamino)pyrimidine-5-carbonitrile a: (S)-enantiomer a-1 and a-2: atropisomers b:(R)-enantiomer b-1 and b-2: atropisomers 111

2,4-diamino-6-((1-(5- methoxy-4-oxo-3- phenyl-3,4- dihydroquinazolin-2-yl)ethyl)amino)pyrimidine- 5-carbonitrile a: (S)-enantiomer b:(R)-enantiomer 112

2-(1-((2,6-diamino-5- cyanopyrimidin-4- yl)amino)ethyl)-3-(3,5-difluorophenyl)-4-oxo- 3,4-dihydroquinazoline- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 113

3-(3-cyano-5- fluorophenyl)-2-(1- ((2,6-diamino-5- cyanopyrimidin-4-yl)amino)ethyl)-4-oxo- 3,4-dihydroquinazoline- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 114

2,4-diamino-6-((1-(3- (3-chloro-5- (difluoromethyl)phenyl)-5-fluoro-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 115

2,4-diamino-6-((1-(5- chloro-3-(3-chloro-5- (difluoromethyl)phenyl)-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 116

2,4-diamino-6-((1-(3- (3- (difluoromethyl)phenyl)- 5-(methylsulfonyl)-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrilea: (S)-enantiomer b: (R)-enantiomer 117

2,4-diamino-6-((1-(3- (3-fluorophenyl)-5- (methylsulfonyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 118

2,4-diamino-6-((1-(3- (3,5- bis(difluoromethyl)phen-yl)-5-fluoro-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 119

2,4-diamino-6-((1-(3- (3,5- bis(difluoromethyl)phen-yl)-5-chloro-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 120

2,4-diamino-6-((1-(5- chloro-3-(3-(2,2- difluoroethyl)phenyl)-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrilea: (S)-enantiomer b: (R)-enantiomer 121

2,4-diamino-6-((1-(3- (3-(2,2- difluoroethyl)phenyl)-5-fluoro-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 122

2-(1-((2,6-diamino-5- cyanopyrimidin-4- yl)amino)ethyl)-4-oxo-3-phenyl-3,4- dihydroquinazoline-8- carbonitrile a: (S)-enantiomer b:(R)-enantiomer 124

2-(1-((2,6-diamino-5- cyanopyrimidin-4- yl)amino)ethyl)-8-fluoro-4-oxo-3-phenyl- 3,4-dihydroquinazoline- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 125

2-(1-((2,6-diamino-5- cyanopyrimidin-4- yl)amino)ethyl)-3-(3,5-difluorophenyl)-8- fluoro-4-oxo-3,4- dihydroquinazoline-5- carbonitrilea: (S)-enantiomer b: (R)-enantiomer 127

5-chloro-2-(1-((2,6- diamino-5- chloropyrimidin-4- yl)amino)ethyl)-8-fluoro-3- phenylquinazolin- 4(3H)-one a: (S)-enantiomer b:(R)-enantiomer 129

2,4-diamino-6-((1-(5- bromo-4-oxo-3-phenyl- 3,4-dihydroquinazolin- 2-yl)ethyl)amino)pyrimidine- 5-carbonitrile a: (S)-enantiomer b:(R)-enantiomer 130

2,4-diamino-6-((1-(5- bromo-3-(3- fluorophenyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 131

2-(1-((2,6-diamino-5- cyanopyrimidin-4- yl)amino)ethyl)-3-(3-fluorophenyl)-4-oxo- 3,4-dihydroquinazoline- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 132

2,4-diamino-6-((3,3,3- trifluoro-1-(6-fluoro-4- oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimi- dine-5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 133

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-6- fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)-3,3,3- trifluoropropyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 135

2,4-diamino-6-((1-(5- chloro-3-(3,5- difluorophenyl)-4-oxo-3,4-dihydroquinazolin- 2-yl)-2- methoxyethyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 136

2,4-diamino-6-((1-(3- (3,5- bis(difluoromethyl)phen-yl)-5-fluoro-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 137

2,4-diamino-6-((1-(3- (3,5- bis(difluoromethyl)phen-yl)-5-chloro-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 138

2-(1-((2,6-diamino-5- cyanopyrimidin-4- yl)amino)ethyl)-3-(3-(difluoromethyl)-5- fluorophenyl)-4-oxo- 3,4-dihydroquinazoline-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 140

2,4-diamino-6-((1-(5- chloro-3-(3,5- difluorophenyl)-6-fluoro-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 141

2,4-diamino-6-((1-(5- chloro-3-(3- (difluoromethyl)-5-fluorophenyl)-6-fluoro- 4-oxo-3,4- dihydroquinazolin-2-yl)ethyl)amino)pyrimidine- 5-carbonitrile a: (S)-enantiomer b:(R)-enantiomer 145

2,4-diamino-6-((1-(5- (2,6- difluorophenyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 146

2,4-diamino-6-((1-(3- (2,6-difluorophenyl)-5- (methylsulfonyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 148

2,4-diamino-6-((1-(5,8- difluoro-3-(3- fluorophenyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 149

2,4-diamino-6-((1-(3- (3-cyanophenyl)-5,8- difluoro-4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 150

2,4-diamino-6-((1-(5,8- difluoro-4-oxo-3- phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimi- dine-5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 151

2,4-diamino-6-((1-(5,8- difluoro-3-(3- fluorophenyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)propyl)amino)pyrimi- dine-5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 152

2,4-diamino-6-((1-(3- (3-cyanophenyl)-5,8- difluoro-4-oxo-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimi- dine-5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 153

2-(1-((2,6-diamino-5- chloropyrimidin-4- yl)amino)ethyl)-3-(3-fluorophenyl)-5- (methylsulfonyl)quina- zolin-4(3H)-one a:(S)-enantiomer b: (R)-enantiomer 154

2-(1-((2,6-diamino-5- cyanopyrimidin-4- yl)amino)ethyl)-6- fluoro-3-(3-fluorophenyl)-4-oxo- 3,4-dihydroquinazoline- 8-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 155

2-(1-((2,6-diamino-5- cyanopyrimidin-4- yl)amino)ethyl)-6-fluoro-4-oxo-3-phenyl- 3,4-dihydroquinazoline- 8-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 156

2,4-diamino-6-((1-(8- methoxy-4-oxo-3- phenyl-3,4- dihydroquinazolin-2-yl)ethyl)amino)pyrimidine- 5-carbonitrile a: (S)-enantiomer b:(R)-enantiomer 159

2-(1-((2,6-diamino-5- cyanopyrimidin-4- yl)amino)ethyl)-4-oxo-3-phenyl-3,4- dihydroquinazoline-6- carbonitrile a: (S)-enantiomer b:(R)-enantiomer 160

2-(1-((2,6-diamino-5- cyanopyrimidin-4- yl)amino)ethyl)-3-(3-(difluoromethyl)phenyl)- 4-oxo-3,4- dihydroquinazoline-8- carbonitrilea: (S)-enantiomer b: (R)-enantiomer 161

2-(1-((2,6-diamino-5- cyanopyrimidin-4- yl)amino)ethyl)-3-(3,5-difluorophenyl)-6- fluoro-4-oxo-3,4- dihydroquinazoline-8- carbonitrilea: (S)-enantiomer b: (R)-enantiomer 162

2-(1-((2,6-diamino-5- cyanopyrimidin-4- yl)amino)ethyl)-4-oxo-3-phenyl-3,4- dihydroquinazoline-5- carboxylic acid a: (S)-enantiomer b:(R)-enantiomer 163

2,4-diamino-6-((1-(5- chloro-3-(3,5- difluorophenyl)-4-oxo-3,4-hydroquinazolin- 2-yl)-3- methylbutyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 164

2,4-diamino-6-((1-(5- chloro-3-(3,5- difluorophenyl)-4-oxo-3,4-dihydroquinazolin- 2-yl)-2- methylbutyl)amino)pyrimidine-5-carbonitrile a: (1S, 2S) b: (1S, 2R) c: (1R, 1R) d: (1R,2S) 165

2,4-diamino-6-((1-(5- chloro-3-(3,5- difluorophenyl)-4-oxo-3,4-dihydroquinazolin- 2-yl)-3,3,3- trifluoropropyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 166

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-5- fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)-3,3,3- trifluoropropyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 167

2,4-diamino-6-((1-(5- chloro-3-(3- cyanophenyl)-4-oxo-3,4-dihydroquinazolin- 2-yl)-3- methylbutyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 168

2,4-diamino-6-((1-(5- chloro-3-(3- fluorophenyl)-4-oxo-3,4-dihydroquinazolin- 2-yl)-3- methylbutyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 175

2,4-diamino-6-((1-(3- (3,5-difluorophenyl)-5- fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)butyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 176

2,4-diamino-6-((1-(5- chloro-3-(3- cyanophenyl)-6-fluoro- 4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 178

2,4-diamino-6-((1-(6- fluoro-3-(3- fluorophenyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)propyl)amino)pyrimi- dine-5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 179

2,4-diamino-6-((1-(5- fluoro-3-(3- fluorophenyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)propyl)amino)pyrimi- dine-5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 181

2,4-diamino-6-((1-(5- chloro-3-(3- cyanophenyl)-8-fluoro- 4-oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 182

2,4-diamino-6-((1-(5- fluoro-3-(3- fluorophenyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 183

2,4-diamino-6-((1-(5- chloro-4-oxo-3-phenyl- 3,4-dihydroquinazolin- 2-yl)ethyl)amino)pyrimidine- 5-carboxamide a: (S)-enantiomer b:(R)-enantiomer 184

2,4-diamino-6-((1-(5- chloro-3-(3-methoxy-4- methylphenyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 185

2,4-diamino-6-((1-(5- chloro-3-(3- methoxyphenyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 186

2,4-diamino-6-((1-(5- chloro-3-(4-fluoro-3- methoxyphenyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 190

2,4-diamino-6-((1-(5- chloro-3-(3- (difluoromethyl)-5-methoxyphenyl)-4-oxo- 3,4-dihydroquinazolin- 2-yl)ethyl)amino)pyrimidine- 5-carbonitrile a: (S)-enantiomer b:(R)-enantiomer 192

2,4-diamino-6-((1-(5- chloro-3-(3-fluoro-5- methoxyphenyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 193

2,4-diamino-6-((1-(5- chloro-3-(3-fluoro-5- (trifluoromethoxy)phen-yl)-4-oxo-3,4- dihydroquinazolin-2- yl)ethyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 194

5-chloro-2-(1-((2,6- diamino-5- fluoropyrimidin-4- yl)amino)ethyl)-3-phenylquinazolin- 4(3H)-one a: (S)-enantiomer b: (R)-enantiomer 195

8-chloro-3-(1-((2,6- diamino-5- chloropyrimidin-4- yl)amino)ethyl)-2-phenylisoquinolin- 1(2H)-one a: (S)-enantiomer b: (R)-enantiomer 196

2,4-diamino-6-((1-(8- chloro-1-oxo-2-phenyl- 1,2-dihydroisoquinolin- 3-yl)ethyl)amino)pyrimidine- 5-carbonitrile a: (S)-enantiomer b:(R)-enantiomer 197

2,4-diamino-6-((1-(5- chloro-4-oxo-3-phenyl- 3,4-dihydroquinazolin-2-yl)-2- methylpropyl)amino) pyrimidine-5-carbonitrile a: (S)-enantiomerb: (R)-enantiomer 198

2,4-diamino-6-((1-(5- chloro-3-(3,5- difluorophenyl)-4-oxo-3,4-dihydroquinazolin- 2-yl)-2- methylpropyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b: (R)-enantiomer 205

2,4-diamino-6-((1-(5- chloro-3-(3-fluoro-5- methoxyphenyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 206

2,4-diamino-6-((1-(5- chloro-3-(3- methoxyphenyl)-4-oxo-3,4-dihydroquinazolin- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer b: (R)-enantiomer 142

2,4-diamino-6-((1-(3- (2-fluorophenyl)-5- (methylsulfonyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer a-1 and a-2: atropisomers b: (R)-enantiomer b-1 and b-2:atropisomers 187

2,4-diamino-6-((1-(5- chloro-3-(5-methoxy-2- methylphenyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer a-1 and a-2: atropisomers b: (R)-enantiomer b-1 and b-2:atropisomers 188

2,4-diamino-6-((1-(5- chloro-3-(5- (difluoromethyl)-2-methylphenyl)-4-oxo- 3,4-dihydroquinazolin- 2-yl)ethyl)amino)pyrimidine- 5-carbonitrile a: (S)-enantiomer a-1 and a-2:atropisomers b: (R)-enantiomer b-1 and b-2: atropisomers 189

2,4-diamino-6-((1-(5- chloro-3-(3- (difluoromethyl)-2-methylphenyl)-4-oxo- 3,4-dihydroquinazolin- 2-yl)ethyl)amino)pyrimidine- 5-carbonitrile a: (S)-enantiomer a-1 and a-2:atropisomers b: (R)-enantiomer b-1 and b-2: atropisomers 191

2,4-diamino-6-((1-(5- chloro-3-(2,5- dimethylphenyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer a-1 and a-2: atropisomers b: (R)-enantiomer b-1 and b-2:atropisomers 199

2,4-diamino-6-((1-(5- chloro-3-(3-fluoro-2- methylphenyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer a-1 and a-2: atropisomers b: (R)-enantiomer b-1 and b-2:atropisomers 200

2,4-diamino-6-((1-(5- chloro-3-(3,5-difluoro- 2-methylphenyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer a-1 and a-2: atropisomers b: (R)-enantiomer b-1 and b-2:atropisomers 201

2,4-diamino-6-((1-(5- chloro-3-(5-fluoro-2- methylphenyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer a-1 and a-2: atropisomers b: (R)-enantiomer b-1 and b-2:atropisomers 202

2,4-diamino-6-((1-(5- chloro-3-(2,3- dimethylphenyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer a-1 and a-2: atropisomers b: (R)-enantiomer b-1 and b-2:atropisomers 203

2,4-diamino-6-((1-(5- chloro-3-(4-fluoro-2,3- dimethylphenyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer a-1 and a-2: atropisomers b: (R)-enantiomer b-1 and b-2:atropisomers 204

2,4-diamino-6-((1-(5- chloro-3-(3,4-difluoro- 2-methylphenyl)-4-oxo-3,4-dihydroquinazolin- 2- yl)ethyl)amino)pyrimidine- 5-carbonitrile a:(S)-enantiomer a-1 and a-2: atropisomers b: (R)-enantiomer b-1 and b-2:atropisomers 207

2,4-diamino-6-((1-(5- chloro-3-(5-fluoro-3- methoxy-2-methylphenyl)-4-oxo- 3,4-dihydroquinazolin- 2-yl)ethyl)amino)pyrimidine- 5-carbonitrile a: (S)-enantiomer a-1 and a-2:atropisomers b: (R)-enantiomer b-1 and b-2: atropisomers

Provided are also compounds of formula (J), (I), (IA-1), (IA-2), (IB-1),(IB-2), (IB-3), or (IB-4), or pharmaceutically acceptable salts,prodrugs, or solvates thereof, in which from 1 to n hydrogen atomsattached to a carbon atom may be replaced by a deuterium atom or D, inwhich n is the number of hydrogen atoms in the molecule. As known in theart, the deuterium atom is a non-radioactive isotope of the hydrogenatom. Such compounds may increase resistance to metabolism, and thus maybe useful for increasing the half-life of the compounds of formula (J),(I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), orpharmaceutically acceptable salts, prodrugs, or solvates thereof, whenadministered to a mammal. See, e.g., Foster, “Deuterium Isotope Effectsin Studies of Drug Metabolism”, Trends Pharmacol. Sci., 5(12):524-527(1984). Such compounds are synthesized by means well known in the art,for example by employing starting materials in which one or morehydrogen atoms have been replaced by deuterium.

Provided are also pharmaceutically acceptable salts, hydrates, solvates,tautomeric forms, polymorphs, and prodrugs of the compounds of formula(J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4).

“Pharmaceutically acceptable salts” include, for example, salts withinorganic acids and salts with an organic acid. In addition, if thecompounds described herein are obtained as an acid addition salt, thefree base can be obtained by basifying a solution of the acid salt.Conversely, if the product is a free base, an addition salt,particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used to prepare nontoxic pharmaceutically acceptable additionsalts.

A “solvate” is formed by the interaction of a solvent and a compound.Solvates of salts of the compounds of formula (J), (I), (IA-1), (IA-2),(IB-1), (IB-2), (IB-3), or (IB-4) are also provided. Hydrates of thecompounds of formula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3),or (IB-4) are also provided.

A “prodrug” includes any compound that becomes a compound of formula(J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4) whenadministered to a subject, e.g., upon metabolic processing of theprodrug.

In certain embodiments, provided are optical isomers, racemates,atropisomers, or other mixtures thereof, of the compounds of formula(J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), orpharmaceutically acceptable salts, prodrugs, or solvates thereof. Inthose situations, the single enantiomer or diastereomer, i.e., opticallyactive form, can be obtained by asymmetric synthesis or by resolution ofthe racemate. Resolution of racemates can be accomplished, for example,by conventional methods such as crystallization in the presence of aresolving agent, or chromatography, using, for example a chiral highpressure liquid chromatography (HPLC) column. In addition, provided arealso Z- and E-forms (or cis- and trans-forms) of the compounds offormula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), orpharmaceutically acceptable salts, prodrugs, or solvates thereof withcarbon-carbon double bonds. Provided are also all tautomeric forms ofthe compounds of formula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2),(IB-3), or (IB-4), or pharmaceutically acceptable salts, prodrugs, orsolvates thereof.

Compositions provided herein that include a compound of formula (J),(I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or apharmaceutically acceptable salt, prodrug, or solvate thereof, mayinclude racemic mixtures, or mixtures containing an enantiomeric excessof one enantiomer or single diastereomers or diastereomeric mixtures.All such isomeric forms of these compounds are expressly included hereinthe same as if each and every isomeric form were specifically andindividually listed.

In certain embodiments, provided herein are also crystalline andamorphous forms of the compounds of formula (J), (I), (IA-1), (IA-2),(IB-1), (IB-2), (IB-3), or (IB-4), or pharmaceutically acceptable salts,prodrugs, or solvates thereof.

In certain embodiments, provided are also chelates, non-covalentcomplexes, and mixtures thereof, of the compounds of formula (J), (I),(IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or pharmaceuticallyacceptable salts, prodrugs, or solvates thereof. A “chelate” is formedby the coordination of a compound to a metal ion at two (or more)points. A “non-covalent complex” is formed by the interaction of acompound and another molecule wherein a covalent bond is not formedbetween the compound and the molecule. For example, complexation canoccur through van der Waals interactions, hydrogen bonding, andelectrostatic interactions (also called ionic bonding).

Therapeutic Uses of the Compounds

The compounds of formula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2),(IB-3), or (IB-4), or a pharmaceutically acceptable salt, prodrug, orsolvate thereof may be used for the treatment of diseases and/orconditions mediated by PI3K isomers, such as MK& Thus, provided hereinare methods for inhibiting one or more PI3K isomers. In one embodiment,provided are methods for inhibiting PI3Kδ activity using a compound offormula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), ora pharmaceutically acceptable salt, prodrug, or solvate thereof. The MKisomers may be selectively or specifically inhibited. Additionally, thecompounds may be used to inhibit PI3K activity therapeutically orprophylactically.

In some embodiments, the methods include administering a compound offormula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), ora pharmaceutically acceptable salt, prodrug, or solvate thereof, in atherapeutically effective amount to a subject (including a human) inneed thereof. The method can be employed to treat a subject who has oris believed to have a disease or condition whose symptoms or pathologyis mediated by PI3Kδ expression or activity.

In addition to the therapeutic uses described herein, certain compoundsof formula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4),or a pharmaceutically acceptable salt, prodrug, or solvate thereof, haveone or more properties selected from: (i) selectivity to any PI3Kisoforms, such as PI3Kδ; (ii) hepatocyte stability; and (iii) potency ina cellular assay. In one embodiment, certain compounds of formula (J),(I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or apharmaceutically acceptable salt, prodrug, or solvate thereof, haveselectivity to any PI3K isoforms, such as PI3Kδ. In other embodiments,certain compounds of formula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2),(IB-3), or (IB-4), or a pharmaceutically acceptable salt, prodrug, orsolvate thereof, have selectivity to at least PI3Kδ. In yet otherembodiments, certain compounds of formula (J), (I), (IA-1), (IA-2),(IB-1), (IB-2), (IB-3), or (IB-4), or a pharmaceutically acceptablesalt, prodrug, or solvate thereof, have one of the properties selectedfrom: (i) selectivity to PI3Kδ; (ii) hepatocyte stability; and (iii)potency in a cellular assay. In yet other embodiments, certain compoundsof formula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4),or a pharmaceutically acceptable salt, prodrug, or solvate thereof,have: selectivity to PI3Kδ and hepatocyte stability; or selectivity toPI3Kδ and potency in a cellular assay: or hepatocyte stability andpotency in a cellular assay. In some embodiments, certain compounds offormula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), ora pharmaceutically acceptable salt, prodrug, or solvate thereof, haveselectivity to PI3Kδ, hepatocyte stability, and potency in a cellularassay.

In another embodiment, certain compounds of formula (J), (I), (IA-1),(IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or a pharmaceuticallyacceptable salt, prodrug, or solvate thereof have hepatocyte stability.Hepatocyte stability of a subject can be determined using any methodscurrently known in the art, including the methods described in theExamples below. For example, hepatocyte stability may be characterizedbased on clearance or half-life. In some embodiments, the half-life isgreater than or about 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8hours, 9 hours, 10 hours, 11 hours, 12 hours, or 15 hours in humanhepatocytes.

In yet another embodiment, certain compounds of formula (J), (I),(IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or a pharmaceuticallyacceptable salt, prodrug, or solvate thereof have potency in a cellularassay. Potency in a cellular assay can be determined using any methodscurrently known in the art, including the methods described in theExamples below. In some embodiments, the activity in the cellular assayis less than 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1nM, 0.1 nM, or 0.01 nM.

For example, certain compounds may have selectivity to at least one PI3Kisomer, including PI3Kδ, and have hepatocyte stability based on ahalf-life of greater than 3 hours.

“Treatment” or “treating” is an approach for obtaining beneficial ordesired results including clinical results. Beneficial or desiredclinical results may include one or more of the following:

a) inhibiting the disease or condition (e.g., decreasing one or moresymptoms resulting from the disease or condition, and/or diminishing theextent of the disease or condition);

b) slowing or arresting the development of one or more clinical symptomsassociated with the disease or condition (e.g., stabilizing the diseaseor condition, preventing or delaying the worsening or progression of thedisease or condition, and/or preventing or delaying the spread (e.g.,metastasis) of the disease or condition); and/or

c) relieving the disease, that is, causing the regression of clinicalsymptoms (e.g., ameliorating the disease state, providing partial ortotal remission of the disease or condition, enhancing effect of anothermedication, delaying the progression of the disease, increasing thequality of life, and/or prolonging survival.

“Prevention” or “preventing” means any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. Compounds may, in some embodiments, be administered to asubject (including a human) who is at risk or has a family history ofthe disease or condition.

“Subject” refers to an animal, such as a mammal (including a human),that has been or will be the object of treatment, observation orexperiment. The methods described herein may be useful in human therapyand/or veterinary applications. In some embodiments, the subject is amammal. In one embodiment, the subject is a human.

The term “therapeutically effective amount” of a compound of formula(J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or apharmaceutically acceptable salt, prodrug, or solvate thereof, means anamount sufficient to effect treatment when administered to a subject, toprovide a therapeutic benefit such as amelioration of symptoms orslowing of disease progression. For example, a therapeutically effectiveamount may be an amount sufficient to decrease a symptom of a disease orcondition responsive to inhibition of PI3Kδ activity. Thetherapeutically effective amount may vary depending on the subject, anddisease or condition being treated, the weight and age of the subject,the severity of the disease or condition, and the manner ofadministering, which can readily be determined by one or ordinary skillin the art.

The term “inhibition” indicates a decrease in the baseline activity of abiological activity or process. “Inhibition of activity of PI3K isomers”or variants thereof refer to a decrease in activity in any PI3K isomer(e.g., alpha, beta, gamma, or delta) as a direct or indirect response tothe presence of a compound of formula (J), (I), (IA-1), (IA-2), (IB-1),(IB-2), (IB-3), or (IB-4), or a pharmaceutically acceptable salt,prodrug, or solvent thereof, relative to the activity of PI3K isomer inthe absence of the compound of formula (J), (I), (IA-1), (IA-2), (IB-1),(IB-2), (IB-3), or (IB-4), or a pharmaceutically acceptable salt,prodrug, or solvent thereof. “Inhibition of PI3Kδ activity” or variantsthereof refer to a decrease in PI3Kδ activity as a direct or indirectresponse to the presence of a compound of formula (J), (I), (IA-1),(IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or a pharmaceuticallyacceptable salt, prodrug, or solvate thereof, relative to the activityof PI3Kδ in the absence of the compound of formula (J), (I), (IA-1),(IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or a pharmaceuticallyacceptable salt, prodrug, or solvate thereof. In some embodiments, theinhibition of PI3Kδ activity may be compared in the same subject priorto treatment, or other subjects not receiving the treatment.

Without wishing to be bound to any theory, the decrease in PI3Kδactivity may be due to the direct interaction of the compound withPI3Kδ, or due to the interaction of the compounds described herein withone or more other factors that in turn affect PI3Kδ activity. Forexample, the presence of the compounds of formula (J), (I), (IA-1),(IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or a pharmaceuticallyacceptable salt, prodrug, or solvate thereof, may decrease PI3Kδactivity by directly binding to the PI3Kδ, by causing (directly orindirectly) another factor to decrease PI3Kδ activity, or by (directlyor indirectly) decreasing the amount of PI3Kδ present in the cell ororganism.

The terms “PI3K isoform selective inhibitor” generally refers to acompound that inhibits the activity of one or more PI3K isoforms moreeffectively than the other remaining PI3K isoforms. By way of example,the term “PI3Kδ selective inhibitor” generally refers to a compound thatinhibits the activity of the PI3Kδ isoform more effectively than otherisoforms of the PI3K family (e.g., PI3K α, β, or γ). The term “PI3Kαselective inhibitor” generally refers to a compound that inhibits theactivity of the PI3Kα isoform more effectively than other isoforms ofthe PI3K family (e.g., PI3K β, δ, or γ). The term “PI3Kβ selectiveinhibitor” generally refers to a compound that inhibits the activity ofthe PI3Kβ isoform more effectively than other isoforms of the PI3Kfamily (e.g., PI3K α, δ, or γ). The term “dual PI3Kα/β selectiveinhibitor generally refers to a compound that inhibits the activity ofthe PI3Kα and PI3Kβ isoforms more effectively than other isoforms of thePI3K family (e.g., PI3K δ or γ).

The relative efficacies of compounds as inhibitors of an enzyme activity(or other biological activity) can be established by determining theconcentrations at which each compound inhibits the activity to apredefined extent and then comparing the results. In one embodiment, theefficacy of a compound as an inhibitor of one or more PI3K isoforms canbe measured by the concentration that inhibits 50% of the activity in abiochemical assay, i.e., the 50% inhibitory concentration or “IC₅₀”.IC₅₀ determinations can be accomplished using conventional techniquesknown in the art, including the techniques describes in the Examplesbelow. In general, an IC₅₀ can be determined by measuring the activityof a given enzyme in the presence of a range of concentrations of thecompound under study. The experimentally obtained values of enzymeactivity may then be plotted against the compound concentrations used.The concentration of the inhibitor that shows 50% enzyme activity (ascompared to the activity in the absence of any inhibitor) is taken asthe IC₅₀ value. Analogously, other inhibitory concentrations can bedefined through appropriate determinations of activity. For example, insome settings it may be desirable to establish a 90% inhibitoryconcentration, i.e., IC₉₀.

In one embodiment, a PI3Kδ selective inhibitor is a compound thatexhibits a 50% inhibitory concentration (IC₅₀) with respect to PI3Kδthat is at least 10-fold, in another aspect at least 20-fold, and inanother aspect at least 30-fold, lower than the IC₅₀ value with respectto any or all of the other Class I PI3K family members. In anotherembodiment, a PI3Kδ selective inhibitor is a compound that exhibits anIC₅₀ with respect to PI3Kδ that is at least 50-fold, in another aspectat least 100-fold, in an additional aspect at least 200-fold, and in yetanother aspect at least 500-fold, lower than the IC₅₀ with respect toany or all of the other PI3K Class I family members. A PI3Kδ selectiveinhibitor is typically administered in an amount such that itselectively inhibits PI3Kδ activity, as described above.

In one embodiment, a PI3Kα selective inhibitor is a compound thatexhibits a 50% inhibitory concentration (IC₅₀) with respect to PI3Kβthat is at least 10-fold, in another aspect at least 20-fold, and inanother aspect at least 30-fold, lower than the IC₅₀ value with respectto any or all of the other Class I PI3K family members. In anotherembodiment, a PI3Kα selective inhibitor is a compound that exhibits anIC₅₀ with respect to PI3Kα that is at least 50-fold, in another aspectat least 100-fold, in an additional aspect at least 200-fold, and in yetanother aspect at least 500-fold, lower than the IC₅₀ with respect toany or all of the other PI3K Class I family members. A PI3Kα selectiveinhibitor is typically administered in an amount such that itselectively inhibits PI3Kα activity, as described above

In one embodiment, a PI3Kβ selective inhibitor is a compound thatexhibits a 50% inhibitory concentration (IC₅₀) with respect to PI3Kβthat is at least 10-fold, in another aspect at least 20-fold, and inanother aspect at least 30-fold, lower than the IC₅₀ value with respectto any or all of the other Class I PI3K family members. In anotherembodiment, a PI3Kβ selective inhibitor is a compound that exhibits anIC₅₀ with respect to PI3Kβ that is at least 50-fold, in another aspectat least 100-fold, in an additional aspect at least 200-fold, and in yetanother aspect at least 500-fold, lower than the IC₅₀ with respect toany or all of the other PI3K Class I family members. A PI3Kβ selectiveinhibitor is typically administered in an amount such that itselectively inhibits PI3Kβ activity, as described above.

In one embodiment, a dual PI3Kα/β selective inhibitor is a compound thatexhibits a 50% inhibitory concentration (IC₅₀) with respect to PI3Kα andPI3Kβ that is at least 10-fold, in another aspect at least 20-fold, andin another aspect at least 30-fold, lower than the IC₅₀ value withrespect to any or all of the other Class I PI3K family members. Inanother embodiment, a dual PI3Kα/β selective inhibitor is a compoundthat exhibits an IC₅₀ with respect to PI3Kα and PI3Kβ that is at least50-fold, in another aspect at least 100-fold, in an additional aspect atleast 200-fold, and in yet another aspect at least 500-fold, lower thanthe IC₅₀ with respect to any or all of the other PI3K Class I familymembers. A dual PI3Kα/β selective inhibitor is typically administered inan amount such that it selectively inhibits PI3Kα and PI3Kβ activity, asdescribed above.

The methods described herein may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human. In this context, the methods described herein may beused therapeutically in an individual. “Ex vivo” means outside of aliving individual. Examples of ex vivo cell populations include in vitrocell cultures and biological samples including fluid or tissue samplesobtained from individuals. Such samples may be obtained by methods wellknown in the art. Exemplary biological fluid samples include blood,cerebrospinal fluid, urine, and saliva. Exemplary tissue samples includetumors and biopsies thereof. In this context, the invention may be usedfor a variety of purposes, including therapeutic and experimentalpurposes. For example, the invention may be used ex vivo to determinethe optimal schedule and/or dosing of administration of a PI3Kδselective inhibitor for a given indication, cell type, individual, andother parameters. Information gleaned from such use may be used forexperimental purposes or in the clinic to set protocols for in vivotreatment. Other ex vivo uses for which the invention may be suited aredescribed below or will become apparent to those skilled in the art. Theselected compounds of formula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2),(IB-3), or (IB-4), or a pharmaceutically acceptable salt, prodrug, orsolvate thereof, may be further characterized to examine the safety ortolerance dosage in human or non-human subjects. Such properties may beexamined using commonly known methods to those skilled in the art.

Compared to other PI3K isoforms, PI3Kδ is generally expressed inhematopoietic cells. Consequently, the direct effects of selectiveinhibitors of PI3Kδ can be observed in hematopoietic cells.Hematopoietic cells typically differentiate into either lymphoidprogenitor cells or myeloid progenitor cells, both of which ultimatelydifferentiate into various mature cell types including leukocytes.Aberrant proliferation of hematopoietic cells of one type ofteninterferes with the production or survival of other hematopoietic celltypes, which can result in compromised immunity, anemia, and/orthrombocytopenia. The methods described herein may treat aberrantproliferation of hematopoietic cells by inhibiting aberrantproliferation of hematopoietic cells. As a result, these methods mayalso ameliorate the symptoms and secondary conditions that result from aprimary effect such as excessive system or localized levels ofleukocytes or lymphocytes.

In some embodiments, the compounds described herein may be used to treatsubjects having various disease states, disorders, and conditions (alsocollectively referred to as “indications”) involving aberrantproliferation of hematopoietic cells (including excessive production oflymphoid progenitor cell-derived cells and/or myeloid progenitorcell-derived cells). Such indications may include, for example,leukemias, lymphomas, myeloproliferative disorders, myelodysplasticsyndromes, and plasma cell neoplasms. In certain embodiments, thecompounds described herein may be used to treat hematologicmalignancies, inflammation, autoimmune disorders, allergic conditions,cardiovascular disease, and autoimmune diseases. In certain embodiments,allergic conditions may include all forms of hypersensitivity.

In other embodiments, the compounds described herein may be used totreat cancers that are mediated by, dependent on or associated with PI3Kactivity, such as PI3Kδ activity. In certain embodiments, the disease isa hematologic malignancy. In certain embodiments, the disease islymphoma, multiple myeloma, or leukemia. In particular embodiments, thehematologic malignancy is leukemia or lymphoma. In specific embodiments,the disease is acute lymphocytic leukemia (ALL), acute myeloid leukemia(AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma(SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD),chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML),multiple myeloma (MM), Hodgkin lymphoma, indolent non-Hodgkin's lymphoma(iNHL), refractory iNHL, non-Hodgkin's lymphoma (NHL), mantle celllymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia(WM), minimal residual disease (MRD), T-cell lymphoma, B-cell lymphoma,diffuse large B-cell lymphoma (DLBCL), T-cell acute lymphoblasticleukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL),lymphoplasmacytic lymphoma, marginal zone lymphoma, or Burkitt lymphoma.In one embodiment, the disease is T-cell acute lymphoblastic leukemia(T-ALL), or B-cell acute lymphoblastic leukemia (B-ALL). It should beunderstood that the non-Hodgkin lymphoma may, in certain embodiments,encompass the indolent B-cell diseases that include, for example,follicular lymphoma, lymphoplasmacytic lymphoma, Waldenstrommacroglobulinemia, and marginal zone lymphoma, as well as the aggressivelymphomas that include, for example, Burkitt lymphoma, diffuse largeB-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).

In other embodiments, the disease is a solid tumor. In particularembodiments, the solid tumor is from pancreatic cancer, bladder cancer,colorectal cancer, breast cancer, prostate cancer, renal cancer,hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer,gastric cancer, esophageal cancer, head and neck cancer, melanoma,neuroendocrine cancers, CNS cancers, brain tumors (e.g., glioma,anaplastic oligodendroglioma, adult glioblastoma multiforme, and adultanaplastic astrocytoma), bone cancer, or soft tissue sarcoma. In someembodiments, the solid tumor is from non-small cell lung cancer,small-cell lung cancer, colon cancer, CNS cancer, melanoma, ovariancancer, renal cancer, prostate cancer, or breast cancer.

In some embodiments, the disease is an autoimmune disease. In particularembodiments, the autoimmune disease is systemic lupus erythematosus(SLE), myestenia gravis, rheumatoid arthritis (RA), acute disseminatedencephalomyelitis, idiopathic thrombocytopenic purpura, multiplesclerosis (MS), Sjoegren's syndrome, psoriasis, autoimmune hemolyticanemia, asthma, or chronic obstructive pulmonary disease (COPD). Inother embodiments, the disease is inflammation. In yet otherembodiments, the disease is excessive or destructive immune reactions,such as asthma, rheumatoid arthritis, multiple sclerosis, chronicobstructive pulmonary disease (COPD), and lupus.

Provided is a method for treating a subject, who has or is suspected ofhaving a disease or condition responsive or believed to be responsive tothe inhibition of PI3Kδ activity by administering to the subject acompound of formula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or(IB-4), or a pharmaceutically acceptable salt, prodrug, or solvatethereof.

Provided is also a method of inhibiting kinase activity of aphosphatidylinositol 3-kinase delta polypeptide by contacting thepolypeptide with a compound of formula (J), (I), (IA-1), (IA-2), (IB-1),(IB-2), (IB-3), or (IB-4), or a pharmaceutically acceptable salt,prodrug, or solvate thereof.

Provided is also a method of disrupting leukocyte function comprisingcontacting the leukocytes with an effective amount of a compound offormula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), ora pharmaceutically acceptable salt, prodrug, or solvate thereof, in asubject in need thereof (e.g., a human).

Provided is also a method of inhibiting a growth or a proliferation ofcancer cells of hematopoietic origin comprising contacting the cancercells with an effective amount of a compound of formula (J), (I),(IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or a pharmaceuticallyacceptable salt, prodrug, or solvate thereof. Also provided is a methodfor increasing sensitivity of cancer cells to chemotherapy, comprisingadministering to a patient undergoing chemotherapy with achemotherapeutic agent an amount a compound of formula (J), (I), (IA-1),(IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or a pharmaceuticallyacceptable salt, prodrug, or solvate thereof, sufficient to increase thesensitivity of cancer cells to the chemotherapeutic agent.

Combination Therapies

In one embodiment, the compounds of the present application (e.g., acompound of formula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or(IB-4), or a pharmaceutically acceptable salt, prodrug, or solvatethereof) may be used in combination with one or more additionaltherapeutic agent that are being used and/or developed to treat cancersor inflammatory disorders. The one or more additional therapeutic agentmay be an inhibitor to PI3K such as PI3Kγ, PI3Kβ, and/or PI3Kα, Januskinase (JAK) such as JAK1, JAK2 and/or JAK3, spleen tyrosine kinase(SYK), Bruton's tyrosine kinase (BTK), bromodomain containing proteininhibitor (BRD) such as BRD4, a lysyl oxidase protein (LOX), lysyloxidase-like protein (LOXL) such as LOXL1-5, matrix metalloprotease(MMP) such as MMP 1-10, adenosine A2B receptor (A2B), isocitratedehydrogenase (IDH) such as IDH1, apoptosis signal-regulating kinase(ASK) such as ASK1, serine/threonine kinase TPL2, discoidin domainreceptor (DDR) such as DDR1 and DDR2, histone deacetylase (HDAC),protein kinase C (PKC), or any combination thereof.

One, two, three, or more of the therapeutic agents (e.g. a PI3Kinhibitor, a JAK inhibitor, a SYK inhibitor, a BTK inhibitor, a BRD4inhibitor, a LOXL2 inhibitor, a MMP9 inhibitor, a A2B inhibitor, an IDHinhibitor, an ASK inhibitor, a TPL2 inhibitor, a DDR1 inhibitor, a TBKinhibitor, a HDAC inhibitor, a PKC inhibitor) may be further used orcombined with a chemotherapeutic agent, an immunotherapeutic agent, aradiotherapeutic agent, an anti-neoplastic agent, an anti-cancer agent,an anti-fibrotic agent, an anti-angiogenic agent, a therapeuticantibody, or any combination thereof.

Chemotherapeutic agents may be categorized by their mechanism of actioninto, for example, the following groups: anti-metabolites/anti-canceragents, such as pyrimidine analogs (floxuridine, capecitabine, andcytarabine); purine analogs, folate antagonists and related inhibitorsantiproliferative/antimitotic agents including natural products such asvinca alkaloid (vinblastine, vincristine) and microtubule such as taxane(paclitaxel, docetaxel), vinblastin, nocodazole, epothilones andnavelbine, epidipodophyllotoxins (etoposide, teniposide); DNA damagingagents (actinomycin, amsacrine, busulfan, carboplatin, chlorambucil,cisplatin, cyclophosphamide, Cytoxan, dactinomycin, daunorubicin,doxorubicin, epirubicin, iphosphamide, melphalan, merchlorehtamine,mitomycin, mitoxantrone, nitrosourea, procarbazine, taxol, taxotere,teniposide, etoposide, triethylenethiophosphoramide); antibiotics suchas dactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin),idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin) and mitomycin; enzymes (L-asparaginase which systemicallymetabolizes L-asparagine and deprives cells which do not have thecapacity to synthesize their own asparagine); antiplatelet agents;antiproliferative/antimitotic alkylating agents such as nitrogenmustards cyclophosphamide and analogs, melphalan, chlorambucil), and(hexamethylmelamine and thiotepa), alkyl nitrosoureas (BCNU) andanalogs, streptozocin), trazenes-dacarbazinine (DTIC);antiproliferative/antimitotic antimetabolites such as folic acid analogs(methotrexate); platinum coordination complexes (cisplatin,oxiloplatinim, carboplatin), procarbazine, hydroxyurea, mitotane,aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen,goserelin, bicalutamide, nilutamide) and aromatase inhibitors(letrozole, anastrozole); anticoagulants (heparin, synthetic heparinsalts and other inhibitors of thrombin); fibrinolytic agents (such astissue plasminogen activator, streptokinase and urokinase), aspirin,dipyridamole, ticlopidine, clopidogrel; antimigratory agents;antisecretory agents (breveldin); immunosuppressives tacrolimussirolimus azathioprine, mycophenolate; compounds (TNP-470, genistein)and growth factor inhibitors (vascular endothelial growth factorinhibitors, fibroblast growth factor inhibitors); angiotensin receptorblocker, nitric oxide donors; anti-sense oligonucleotides; antibodies(trastuzumab, rituximab); cell cycle inhibitors and differentiationinducers (tretinoin); inhibitors, topoisomerase inhibitors (doxorubicin(adriamycin), daunorubicin, dactinomycin, eniposide, epirubicin,etoposide, idarubicin, irinotecan and mitoxantrone, topotecan,irinotecan, camptothesin), corticosteroids (cortisone, dexamethasone,hydrocortisone, methylpednisolone, prednisone, and prenisolone); growthfactor signal transduction kinase inhibitors; dysfunction inducers,toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetellapertussis adenylate cyclase toxin, or diphtheria toxin, and caspaseactivators; and chromatin.

As used herein the term “chemotherapeutic agent” or “chemotherapeutic”(or “chemotherapy,” in the case of treatment with a chemotherapeuticagent) may encompass any non-proteinaceous (e.g., non-peptidic) chemicalcompound useful in the treatment of cancer. Examples of chemotherapeuticagents include alkylating agents such as thiotepa and cyclophosphamide;alkyl sulfonates such as busulfan, improsulfan and piposulfan;aziridines such as benzodopa, carboquone, meturedopa, and uredopa;emylerumines and memylamelamines including alfretamine,triemylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimemylolomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (includingsynthetic analogue topotecan); bryostatin; callystatin; CC-1065(including its adozelesin, carzelesin and bizelesin syntheticanalogues); cryptophycins (articularly cryptophycin 1 and cryptophycin8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189and CBI-TMI); eleutherobin; pancratistatin; a sarcodictyin;spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine,cholophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureassuch as carmustine, chlorozotocin, foremustine, lomustine, nimustine,ranimustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, especially calicheamicin gammaII and calicheamicin phiI1,see, e.g., Agnew, Chem. Intl. Ed. Engl, 33:183-186 (1994); dynemicin,including dynemicin A; bisphosphonates, such as clodronate; anesperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antibiotic chromomophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, carrninomycin, carzinophilin, chromomycins, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin(including morpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as demopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogues such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replinisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformthine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine;maytansinoids such as maytansine and ansamitocins; mitoguazone;mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin;losoxantrone; fluoropyrimidine; folinic acid; podophyllinic acid;2-ethylhydrazide; procarbazine; PSK®; razoxane; rhizoxin; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-tricUorotriemylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethane; vindesine;dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman;gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiopeta; taxoids,e.g., paclitaxel (TAXOL®) and docetaxel (TAXOTERE®); chlorambucil;gemcitabine (Gemzar®); 6-thioguanine; mercaptopurine; methotrexate;platinum analogs such as cisplatin and carboplatin; vinblastine;platinum; etoposide (VP-16); ifosfamide; mitroxantrone; vancristine;vinorelbine (Navelbine®); novantrone; teniposide; edatrexate;daunomycin; aminopterin; xeoloda; ibandronate; CPT-11; topoisomeraseinhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such asretinoic acid; capecitabine; FOLFIRI (fluorouracil, leucovorin, andirinotecan) and pharmaceutically acceptable salts, acids or derivativesof any of the above. One or more chemotherapeutic agent are used orincluded in the present application. For example, gemcitabine,nab-paclitaxel, and gemcitabine/nab-paclitaxel are used with the JAKinhibitor and/or PI3Kδ inhibitor for treating hyperproliferativedisorders.

Chemotherapeutic agents may also include, for example, anti-hormonalagents that act to regulate or inhibit hormone action on tumors such asanti-estrogens and selective estrogen receptor modulators (SERMs),including, for example, tamoxifen (including Nolvadex™), raloxifene,droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018,onapristone, and toremifene (Fareston®); inhibitors of the enzymearomatase, which regulates estrogen production in the adrenal glands,such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrolacetate (Megace®), exemestane, formestane, fadrozole, vorozole(Rivisor®), letrozole (Femara®), and anastrozole (Arimidex®.); andanti-androgens such as flutamide, nilutamide, bicalutamide, leuprohde,and goserelin; and pharmaceutically acceptable salts, acids orderivatives of any of the above.

The anti-angiogenic agents include, but are not limited to, retinoidacid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN®,ENDOSTATIN®, suramin, squalamine, tissue inhibitor ofmetalloproteinase-1, tissue inhibitor of metalloproternase-2,plasminogen activator inhibitor-1, plasminogen activator inbibitor-2,cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), plateletfactor 4, protamine sulphate (clupeine), sulphated chitin derivatives(prepared from queen crab shells), sulphated polysaccharidepeptidoglycan complex (sp-pg), staurosporine, modulators of matrixmetabolism, including for example, proline analogs((1-azetidine-2-carboxylic acid (LACA), cishydroxyproline,d,I-3,4-dehydroproline, thiaproline, .alpha.-dipyridyl,beta-aminopropionitrile fumarate,4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone; methotrexate, mitoxantrone,heparin, interferons, 2 macroglobulin-serum, chimp-3, chymostatin,beta-cyclodextrin tetradecasulfate, eponemycin; fumagillin, gold sodiumthiomalate, d-penicillamine (CDPT), beta-1-anticollagenase-serum,alpba-2-antiplasmin, bisantrene, lobenzarit disodium,n-2-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”,thalidomide; angiostatic steroid, cargboxynaminolmidazole;metalloproteinase inhibitors such as BB94. Other anti-angiogenesisagents include antibodies, preferably monoclonal antibodies againstthese angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGFisoforms, VEGF-C, HGF/SF and Ang-1/Ang-2. See Ferrara N. and Alitalo, K.“Clinical application of angiogenic growth factors and their inhibitors”(1999) Nature Medicine 5:1359-1364.

The anti-fibrotic agents include, but are not limited to, the compoundssuch as beta-aminoproprionitrile (BAPN), as well as the compoundsdisclosed in U.S. Pat. No. 4,965,288 to Palfreyman, et al., issued Oct.23, 1990, entitled “Inhibitors of lysyl oxidase,” relating to inhibitorsof lysyl oxidase and their use in the treatment of diseases andconditions associated with the abnormal deposition of collagen; U.S.Pat. No. 4,997,854 to Kagan, et al., issued Mar. 5, 1991, entitled“Anti-fibrotic agents and methods for inhibiting the activity of lysyloxidase in situ using adjacently positioned diamine analogue substrate,”relating to compounds which inhibit LOX for the treatment of variouspathological fibrotic states, which are herein incorporated byreference. Further exemplary inhibitors are described in U.S. Pat. No.4,943,593 to Palfreyman, et al., issued Jul. 24, 1990, entitled“Inhibitors of lysyl oxidase,” relating to compounds such as2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine; as well as, e.g.,U.S. Pat. No. 5,021,456; U.S. Pat. No. 5,5059,714; U.S. Pat. No.5,120,764; U.S. Pat. No. 5,182,297; U.S. Pat. No. 5,252,608 (relating to2-(1-naphthyloxymemyl)-3-fluoroallylamine); and U.S. Patent ApplicationNo. 2004/0248871, which are herein incorporated by reference. Exemplaryanti-fibrotic agents also include the primary amines reacting with thecarbonyl group of the active site of the lysyl oxidases, and moreparticularly those which produce, after binding with the carbonyl, aproduct stabilized by resonance, such as the following primary amines:emylenemamine, hydrazine, phenylhydrazine, and their derivatives,semicarbazide, and urea derivatives, aminonitriles, such asbeta-aminopropionitrile (BAPN), or 2-nitroethylamine, unsaturated orsaturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine,2-trifluoroethylamine, 3-bromopropylamine, p-halobenzylamines,selenohomocysteine lactone. Also, the anti-fibrotic agents are copperchelating agents, penetrating or not penetrating the cells. Exemplarycompounds include indirect inhibitors such compounds blocking thealdehyde derivatives originating from the oxidative deamination of thelysyl and hydroxylysyl residues by the lysyl oxidases, such as thethiolamines, in particular D-penicillamine, or its analogues such as2-amino-5-mercapto-5-methylhexanoic acid,D-2-amino-3-methyl-3((2-acetamidoethyl)dithio)butanoic acid,p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid,sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate,2-acetamidoethyl-2-acetamidoethanethiol sulphanate,sodium-4-mercaptobutanesulphinate trihydrate.

The immunotherapeutic agents include and are not limited to therapeuticantibodies suitable for treating patients; such as abagovomab,adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab,anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab,bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab,cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab,daratumumab, drozitumab, duligotumab, dusigitumab, detumomab,dacetuzumab, dalotuzumab, ecromeximab, elotuzumab, ensituximab,ertumaxomab, etaracizumab, farietuzumab, ficlatuzumab, figitumumab,flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab,glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab,inotuzumab, intetumumab, ipilimumab, iratumumab, labetuzumab,lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab,matuzumab, milatuzumab, minretumomab, mitumomab, moxetumomab,narnatumab, naptumomab, necitumumab, nimotuzumab, nofetumomabn,ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab,oregovomab, panitumumab, parsatuzumab, patritumab, pemtumomab,pertuzumab, pintumomab, pritumumab, racotumomab, radretumab,rilotumumab, rituximab, robatumumab, satumomab, sibrotuzumab,siltuximab, simtuzumab, solitomab, tacatuzumab, taplitumomab,tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab,tucotuzumab, ublituximab, veltuzumab, vorsetuzumab, votumumab,zalutumumab, CC49 and 3F8. The exemplified therapeutic antibodies may befurther labeled or combined with a radioisotope particle, such as indiumIn 111, yttrium Y 90, iodine 1-131.

The application also provides method for treating a subject who isundergoing one or more standard therapies, such as chemotherapy,radiotherapy, immunotherapy, surgery, or combination thereof.Accordingly, one or more therapeutic agent or inhibitors may beadministered before, during, or after administration of chemotherapy,radiotherapy, immunotherapy, surgery or combination thereof.

In certain embodiments, the subject may be a human who is (i)substantially refractory to at least one chemotherapy treatment, or (ii)in relapse after treatment with chemotherapy, or both (i) and (ii). Insome of embodiments, the subject is refractory to at least two, at leastthree, or at least four chemotherapy treatments (including standard orexperimental chemotherapies).

In certain embodiments, the subject is refractory to at least one, atleast two, at least three, or at least four chemotherapy treatment(including standard or experimental chemotherapy) selected fromfludarabine, rituximab, obinutuzumab, alkylating agents, alemtuzumab andother chemotherapy treatments such as CHOP (cyclophosphamide,doxorubicin, vincristine, prednisone); R-CHOP (rituximab-CHOP);hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin,dexamethasone, methotrexate, cytarabine); R-hyperCVAD(rituximab-hyperCVAD); FCM (fludarabine, cyclophosphamide,mitoxantrone); R-FCM (rituximab, fludarabine, cyclophosphamide,mitoxantrone); bortezomib and rituximab; temsirolimus and rituximab;temsirolimus and Velcade®; Iodine-131 tositumomab (Bexxar®) and CHOP;CVP (cyclophosphamide, vincristine, prednisone); R-CVP (rituximab-CVP);ICE (iphosphamide, carboplatin, etoposide); R-ICE (rituximab-ICE); FCR(fludarabine, cyclophosphamide, rituximab); FR (fludarabine, rituximab);and D.T. PACE (dexamethasone, thalidomide, cisplatin, Adriamycin®,cyclophosphamide, etoposide).

Other examples of chemotherapy treatments (including standard orexperimental chemotherapies) are described below. In addition, treatmentof certain lymphomas is reviewed in Cheson, B. D., Leonard, J. P.,“Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's Lymphoma” The NewEngland Journal of Medicine 2008, 359(6), p. 613-626; and Wierda, W. G.,“Current and Investigational Therapies for Patients with CLL” Hematology2006, p. 285-294. Lymphoma incidence patterns in the United States isprofiled in Morton, L. M., et al. “Lymphoma Incidence Patterns by WHOSubtype in the United States, 1992-2001” Blood 2006, 107(1), p. 265-276.

Examples of immunotherapeutic agents treating lymphoma or leukemiainclude, but are not limited to, rituximab (such as Rituxan),alemtuzumab (such as Campath, MabCampath), anti-CD19 antibodies,anti-CD20 antibodies, anti-MN-14 antibodies, anti-TRAIL, Anti-TRAIL DR4and DR5 antibodies, anti-CD74 antibodies, apolizumab, bevacizumab,CHIR-12.12, epratuzumab (hLL2-anti-CD22 humanized antibody), galiximab,ha20, ibritumomab tiuxetan, lumiliximab, milatuzumab, ofatumumab,PRO131921, SGN-40, WT-1 analog peptide vaccine, WT1 126-134 peptidevaccine, tositumomab, autologous human tumor-derived HSPPC-96, andveltuzumab. Additional immunotherapy agents includes using cancervaccines based upon the genetic makeup of an individual patient's tumor,such as lymphoma vaccine example is GTOP-99 (MyVax®).

Examples of chemotherapy agents for treating lymphoma or leukemiainclude aldesleukin, alvocidib, antineoplaston AS2-1, antineoplastonA10, anti-thymocyte globulin, amifostine trihydrate, aminocamptothecin,arsenic trioxide, beta alethine, Bcl-2 family protein inhibitor ABT-263,BMS-345541, bortezomib (Velcade®), bryostatin 1, busulfan, carboplatin,campath-1H, CC-5103, carmustine, caspofungin acetate, clofarabine,cisplatin, Cladribine (Leustarin), Chlorambucil (Leukeran), Curcumin,cyclosporine, Cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin),cytarabine, denileukin diftitox, dexamethasone, DT PACE, docetaxel,dolastatin 10, Doxorubicin (Adriamycin®, Adriblastine), doxorubicinhydrochloride, enzastaurin, epoetin alfa, etoposide, Everolimus(RAD001), fenretinide, filgrastim, melphalan, mesna, Flavopiridol,Fludarabine (Fludara), Geldanamycin (17-AAG), ifosfamide, irinotecanhydrochloride, ixabepilone, Lenalidomide (Revlimid®, CC-5013),lymphokine-activated killer cells, melphalan, methotrexate, mitoxantronehydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine,oblimersen (Genasense) Obatoclax (GX15-070), oblimersen, octreotideacetate, omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991,PEGylated liposomal doxorubicin hydrochloride, pegfilgrastim, Pentstatin(Nipent), perifosine, Prednisolone, Prednisone, R-roscovitine(Selicilib, CYC202), recombinant interferon alfa, recombinantinterleukin-12, recombinant interleukin-11, recombinant flt3 ligand,recombinant human thrombopoietin, rituximab, sargramostim, sildenafilcitrate, simvastatin, sirolimus, Styryl sulphones, tacrolimus,tanespimycin, Temsirolimus (CC1-779), Thalidomide, therapeuticallogeneic lymphocytes, thiotepa, tipifarnib, Velcade® (bortezomib orPS-341), Vincristine (Oncovin), vincristine sulfate, vinorelbineditartrate, Vorinostat (SAHA), vorinostat, and FR (fludarabine,rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine,prednisone), CVP (cyclophosphamide, vincristine and prednisone), FCM(fludarabine, cyclophosphamide, mitoxantrone), FCR (fludarabine,cyclophosphamide, rituximab), hyperCVAD (hyperfractionatedcyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate,cytarabine), ICE (iphosphamide, carboplatin and etoposide), MCP(mitoxantrone, chlorambucil, and prednisolone), R-CHOP (rituximab plusCHOP), R-CVP (rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE(rituximab-ICE), and R-MCP (R-MCP).

The therapeutic treatments can be supplemented or combined with any ofthe abovementioned therapies with stem cell transplantation ortreatment. One example of modified approach is radioimmunotherapy,wherein a monoclonal antibody is combined with a radioisotope particle,such as indium In 111, yttrium Y 90, iodine 1-131. Examples ofcombination therapies include, but are not limited to, Iodine-131tositumomab)(Bexxar®, Yttrium-90 ibritumomab tiuxetan)(Zevalin®, Bexxar®with CHOP.

Other therapeutic procedures include peripheral blood stem celltransplantation, autologous hematopoietic stem cell transplantation,autologous bone marrow transplantation, antibody therapy, biologicaltherapy, enzyme inhibitor therapy, total body irradiation, infusion ofstem cells, bone marrow ablation with stem cell support, invitro-treated peripheral blood stem cell transplantation, umbilical cordblood transplantation, immunoenzyme technique, pharmacological study,low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery,radiation therapy, and nonmyeloablative allogeneic hematopoietic stemcell transplantation.

Kits

Provided herein are also kits that include a compound of formula (J),(I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or apharmaceutically acceptable salt, prodrug, or solvate thereof, andsuitable packaging. In one embodiment, a kit further includesinstructions for use. In one aspect, a kit includes a compound offormula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), ora pharmaceutically acceptable salt, prodrug, or solvate thereof, and alabel and/or instructions for use of the compounds in the treatment ofthe indications, including the diseases or conditions, described herein.

Provided herein are also articles of manufacture that include a compoundof formula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4),or a pharmaceutically acceptable salt, prodrug, or solvate thereof, in asuitable container. The container may be a vial, jar, ampoule, preloadedsyringe, and intravenous bag.

Pharmaceutical Compositions and Modes of Administration

Compounds provided herein are usually administered in the form ofpharmaceutical compositions. Thus, provides herein are alsopharmaceutical compositions that contain one or more of the compounds offormula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), ora pharmaceutically acceptable salt, prodrug, or solvate thereof, and oneor more pharmaceutically acceptable vehicles selected from carriers,adjuvants and excipients. Suitable pharmaceutically acceptable vehiclesmay include, for example, inert solid diluents and fillers, diluents,including sterile aqueous solution and various organic solvents,permeation enhancers, solubilizers and adjuvants. Such compositions areprepared in a manner well known in the pharmaceutical art. See, e.g.,Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia,Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rdEd. (G. S. Banker & C. T. Rhodes, Eds.).

The pharmaceutical compositions may be administered in either single ormultiple doses. The pharmaceutical composition may be administered byvarious methods including, for example, rectal, buccal, intranasal andtransdermal routes. In certain embodiments, the pharmaceuticalcomposition may be administered by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant. In certainembodiments, the compound of formula (J), (I), (IA-1), (IA-2), (IB-1),(IB-2), (IB-3), or (IB-4), or a pharmaceutically acceptable salt,prodrug, or solvate thereof, is administered intraveneously,intramuscularly, parenterally, nasally or orally.

One mode for administration is parenteral, for example, by injection.The forms in which the pharmaceutical compositions described herein maybe incorporated for administration by injection include, for example,aqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles.

Oral administration may be another route for administration of thecompounds described herein. Administration may be via, for example,capsule or enteric coated tablets. In making the pharmaceuticalcompositions that include at least one compound of formula (J), (I),(IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or a pharmaceuticallyacceptable salt, prodrug, or solvate thereof, the active ingredient isusually diluted by an excipient and/or enclosed within such a carrierthat can be in the form of a capsule, sachet, paper or other container.When the excipient serves as a diluent, it can be in the form of asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules, sterileinjectable solutions, and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions that include at least one compound of formula (J), (I),(IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or a pharmaceuticallyacceptable salt, prodrug, or solvate thereof, can be formulated so as toprovide quick, sustained or delayed release of the active ingredientafter administration to the subject by employing procedures known in theart. Controlled release drug delivery systems for oral administrationinclude osmotic pump systems and dissolutional systems containingpolymer-coated reservoirs or drug-polymer matrix formulations. Examplesof controlled release systems are given in U.S. Pat. Nos. 3,845,770;4,326,525; 4,902,514; and 5,616,345. Another formulation for use in themethods of the present invention employs transdermal delivery devices(“patches”). Such transdermal patches may be used to provide continuousor discontinuous infusion of the compounds described herein incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of formula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or(IB-4), or a pharmaceutically acceptable salt, prodrug, or solvatethereof. When referring to these preformulation compositions ashomogeneous, the active ingredient may be dispersed evenly throughoutthe composition so that the composition may be readily subdivided intoequally effective unit dosage forms such as tablets, pills and capsules.

Exemplary unit dosage levels of a compound of formula (J), (I), (IA-1),(IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or a pharmaceuticallyacceptable salt, prodrug, or solvate thereof, for a human subject may,in certain variations, be between about 0.01 mg to about 1000 mg,between about 1 mg to about 15 mg, or between about 50 mg to about 200mg, or about 5 mg, about 10 mg, about 15 mg, about 25 mg, about 50 mg,about 75 mg, about 100 mg, about 125 mg, or about 150 mg, or about 175mg, about 200 mg, or about 250 mg.

The tablets or pills of the compounds described herein may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can include an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation may include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect. In otherembodiments, compositions in pharmaceutically acceptable solvents may benebulized by use of inert gases. Nebulized solutions may be inhaleddirectly from the nebulizing device or the nebulizing device may beattached to a facemask tent, or intermittent positive pressure breathingmachine. Solution, suspension, or powder compositions may beadministered, preferably orally or nasally, from devices that deliverthe formulation in an appropriate manner.

Dosing

The specific dose level of a compound of formula (J), (I), (IA-1),(IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), for any particular subjectwill depend upon a variety of factors including the activity of thespecific compound employed, the age, body weight, general health, sex,diet, time of administration, route of administration, and rate ofexcretion, drug combination and the severity of the particular diseasein the subject undergoing therapy. For example, a dosage may beexpressed as a number of milligrams of a compound of formula (J), (I),(IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4) per kilogram of thesubject's body weight (mg/kg). Dosages of between about 0.1 and 150mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kgmay be appropriate. In other embodiments a dosage of between 0.5 and 60mg/kg may be appropriate. Normalizing according to the subject's bodyweight is particularly useful when adjusting dosages between subjects ofwidely disparate size, such as occurs when using the drug in bothchildren and adult humans or when converting an effective dosage in anon-human subject such as dog to a dosage suitable for a human subject.

The daily dosage may also be described as a total amount of a compoundof formula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4)administered per dose or per day. Daily dosage of a compound of formula(J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4) may bebetween about 1 mg/day and 4,000 mg/day, between about 2,000 mg/day to4,000 mg/day, between about 1 mg/day to 2,000 mg/day, between about 1mg/day to 1,000 mg/day, between about 10 mg/day to 500 mg/day, betweenabout 20 mg/day to 500 mg/day, between about 50 mg/day to 300 mg/day,between about 75 mg/day to 200 mg/day, between about 15 mg/day to 150mg/day, or between 1 mg/day and 15 mg/day.

When administered orally, the total daily dosage for a human subject maybe between 1 mg and 1,000 mg, between about 10-500 mg/day, between about50-300 mg/day, between about 75-200 mg/day, or between about 100-150mg/day.

The compounds of formula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2),(IB-3), or (IB-4) or the compositions thereof may be administered once,twice, three, or four times daily, using any suitable mode describedabove. Also, administration or treatment with the compounds formula (J),(I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4) may be continuedfor a number of days; for example, commonly treatment would continue forat least 7 days, 14 days, or 28 days, for one cycle of treatment.Treatment cycles are well known in cancer chemotherapy, and arefrequently alternated with resting periods of about 1 to 28 days,commonly about 7 days or about 14 days, between cycles. The treatmentcycles, in other embodiments, may also be continuous.

In a particular embodiment, the method comprises administering to thesubject an initial daily dose of about 1 to 500 mg of a compound offormula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4) andincreasing the dose by increments until clinical efficacy is achieved.Increments of about 5, 10, 25, 50, or 100 mg can be used to increase thedose. The dosage can be increased daily, every other day, twice perweek, or once per week.

Synthesis of the Compounds of Formula (I)

The compounds of formula (J), (I), (IA-1), (IA-2), (IB-1), (IB-2),(IB-3), or (IB-4) may be prepared using the methods disclosed herein androutine modifications thereof, which will be apparent given thedisclosure herein and methods well known in the art. Conventional andwell-known synthetic methods may be used in addition to the teachingsherein. The synthesis of typical compounds described herein may beaccomplished as described in the following examples. If available,reagents may be purchased commercially, e.g., from Sigma Aldrich orother chemical suppliers.

General Synthesis

Typical embodiments of compounds described herein may be synthesizedusing the general reaction schemes described below. It will be apparentgiven the description herein that the general schemes may be altered bysubstitution of the starting materials with other materials havingsimilar structures to result in products that are correspondinglydifferent. Descriptions of syntheses follow to provide numerous examplesof how the starting materials may vary to provide correspondingproducts. Given a desired product for which the substituent groups aredefined, the necessary starting materials generally may be determined byinspection. Starting materials are typically obtained from commercialsources or synthesized using published methods. For synthesizingcompounds which are embodiments described in the present disclosure,inspection of the structure of the compound to be synthesized willprovide the identity of each substituent group. The identity of thefinal product will generally render apparent the identity of thenecessary starting materials by a simple process of inspection, giventhe examples herein.

Synthetic Reaction Parameters

The terms “solvent”, “inert organic solvent”, or “inert solvent” referto a solvent inert under the conditions of the reaction being describedin conjunction therewith (including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, pyridine and the like). Unless specified to the contrary, thesolvents used in the reactions of the present invention are inertorganic solvents, and the reactions are carried out under an inert gas,preferably nitrogen.

The term “q.s.” means adding a quantity sufficient to achieve a statedfunction, e.g., to bring a solution to the desired volume (i.e., 100%).

Compounds of Formula I

One method of preparing compounds of formula (I) is shown in ReactionScheme I.

Step 1—Preparation of a Compound of Formula (1)

The compound of formula (1) can be made by combining compounds (A), (B)and (C) in the presence of a dehydrating agent. Compounds (A), (B) and(C) are commercially available or can be made by methods known in theart. With respect to compound (A), R¹ is as defined herein. With respectto compound (B), R³ is as defined herein. With respect to compound (C),R² is as defined herein. Compound (A) can be mixed with Compound (B) inthe presence of a coupling agent such as diphenyl phosphite in a solventsuch as pyridine. After stirring at a temperature between ambient and100° C. for between 1 and 5 hours, compound (C) is added. After furtherstirring at a temperature between ambient and 100° C. for between 5 and24 hours, the reaction mixture is allowed to cool to room temperature.To extract the compound of formula (1), an organic solvent such as ethylacetate (EtOAc) may be added, followed by washing with, mild acid,water, and brine. The organic phase can be concentrated to obtain thecompound of formula (1). The compound of formula (1) may be purified byany suitable methods known in the art, such as chromatography on silicagel. Alternatively, the compound of formula (1) may be used in the nextstep without purification.

Step 2—Preparation of a Compound of Formula (2)

The compound of formula (2) can be made by removing the protectinggroup(s) from the compound of formula (1). The compound of formula (1)is dissolved in a suitable solvent and treated with a suitable acid.Suitable solvents may include, for example, dichloromethane, dioxane, orother suitable solvents. Suitable acids may include, for example,trifluoroacetic acid, hydrochloric acid, or boron tribromide (BBr₃). Thereaction can be carried out at temperatures between −78° C. to ambienttemperature. On reaction completion, solvent is removed to obtain thecompound of formula (2). In the case of a reaction using BBr₃ thereaction may first be treated with MeOH before an aqueous work-up toobtain a compound of formula (2).

Step 3—Preparation of a Compound of Formula (3)

The compound of formula (3) can be made by treating5-substituted-2,4,6-trihalopyrimidine with ammonium hydroxide in asuitable solvent such as dioxane, where the halo is either chloro orfluoro. The reaction is carried out at an elevated temperature between30 and 80° C. for a suitable time, typically between 2 and 8 hours orwhen the reaction is complete. Upon completion, water is added to thecooled solution, and the precipitate is collected by filtration. Thenitrile can be converted to the carboxamide under standard conditions.

Step 4—Preparation of a Compound of Formula (I)

The compound of formula (I) can generally be prepared by couplingcompound of formula (2) and compound of formula (3) in the presence of asuitable base in a suitable solvent. An example of a suitable base isdiisopropylethylamine. An example of a suitable solvent isN-methylpyrrolidone (NMP). The reaction is typically performed at atemperature between 50° C. to 150° C. for about 30 minutes to 24 hours.In some instance, the reaction can be performed at a temperature between20° C. to 100° C. for about 12 hours to 120 hours. Alternatively thereaction can be performed in a microwave at a temperature between 100°C. to 150° C. for about 30 minutes to 24 hours. Water can be added toquench the reaction upon completion, and the precipitate may be filteredand then dissolved in an organic solvent such as dichloromethane (DCM).The product can be isolated by methods known in the art, for example byremoval of solvent under reduced pressure. The product can be purifiedusing any suitable methods known in the art, for example, chromatographyof the residue on a silica column.

It should be understood that the compounds of formula (J) can beprepared according to the methods provided in Reaction Scheme 1,starting from materials known to one of skill in the art.

Example 1 Preparation of a Compound of Formula (1)

A. Preparation of a Compound of Formula (1) in which n is 1, R¹ isChloro, m is 0, and R³ is Methyl

Diphenyl phosphite (1.9 mL, 10 mmol) was added to a solution of2-amino-6-chlorobenzoic acid (495 mg, 2.9 mmol) and(S)-2-(tert-butoxycarbonylamino)propanoic acid (710 mg, 3.77 mmol) inpyridine (3 mL). The reaction mixture was stirred at 40° C. for 2 hours.Aniline (274 mg, 3.48 mmol) was then added to the reaction mixture,which was then stirred at 55° C. for 12 hours. The reaction mixture wascooled to room temperature. This mixture was then diluted with EtOAc (50mL), washed with 1N aqueous HCl (2×50 mL), brine (50 mL), and dried oversodium sulfate. The organics layer was filtered and concentrated invacuuo to afford material which was purified by column chromatography onSiO₂ eluting with EtOAc in hexanes (0-50%) to afford (S)-tert-butyl1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate asa solid. ES/MS m/z=400.1 (M+H±).

B. Preparation of a Compound of Formula (1), Varying R¹, R², and R³

Following the procedure described in Example lA and Reaction Scheme I,but varying the R¹, R² and R³ substituents, other compounds of formula(1) were prepared including:

(S)-tert-butyl1-(8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate,ES/MS m/z=384.1 (M+H⁺);

(S)-tert-butyl1-(5,8-dichloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate,ES/MS m/z=434.2 (M+H⁺);

(S)-tert-butyl1-(5-chloro-8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate,ES/MS m/z=418.1 (M+H⁺);

(S)-tert-butyl1-(8-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate,ES/MS m/z=400.1 (M+H⁺);

(S)-tert-butyl1-(5,8-difluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate,ES/MS m/z=402.1 (M+H⁺);

(S)-tert-butyl1-(5-chloro-4-oxo-3-(3,5-difluorophenyl)-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-chloro-4-oxo-3-(3,5-difluorophenyl)-3,4-dihydroquinazolin-2-yl)propylcarbamate;

(S)-tert-butyl1-(5-fluoro-4-oxo-3-(3,5-difluorophenyl)-3,4-dihydroquinazolin-2-yl)propylcarbamate;

(S)-tert-butyl1-(5-chloro-4-oxo-3-(3-fluorophenyl)-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-fluoro-4-oxo-3-(3,5-difluorophenyl)-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(6-fluoro-4-oxo-3-(3,5-difluorophenyl)-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(6-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-chloro-3-(3-cyanophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(6-fluoro-3-(3-cyanophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(6-fluoro-3-(3-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(8-fluoro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3,5-difluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3,5-difluorophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propylcarbamate;

(S)-tert-butyl1-(3-(3,5-difluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)propylcarbamate;

(S)-tert-butyl1-(3-(3,5-difluorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)propylcarbamate;

(S)-tert-butyl1-(3-(3,5-difluorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5,8-dichloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-chloro-3-(3,5-dicyanophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-chloro-3-(3-cyano-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-hydroxy-3-phenyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5,8-difluoro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-chloro-3-(3,5-difluorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3-cyano-5-fluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-methyl-3-phenyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3,5-difluorophenyl)-8-fluoro-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-chloro-3-(3,5-dimethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(6,7-difluoro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(8-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(8-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propylcarbamate;

(S)-tert-butyl1-(5-(difluoromethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-(difluoromethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propylcarbamate;

(S)-tert-butyl1-(3-(3,5-difluorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propylcarbamate;

(S)-tert-butyl1-(3-(3,5-difluorophenyl)-5,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propylcarbamate;

(S)-tert-butyl1-(3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3,5-difluorophenyl)-5,6-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propylcarbamate;

(S)-tert-butyl1-(3-(3,5-difluorophenyl)-5,6-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-3-(2-(1-aminoethyl)-8-fluoro-5-methyl-4-oxoquinazolin-3(4H)-yl)-5-fluorobenzonitrile;

(S)-tert-butyl1-(3-(3-cyano-5-fluorophenyl)-8-fluoro-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-chloro-3-(3-cyano-5-fluorophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3,5-difluorophenyl)-6,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propylcarbamate;

(S)-tert-butyl1-(3-(3,5-difluorophenyl)-6,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3-cyano-5-fluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-fluoro-3-(3-fluoro-5-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3,5-difluorophenyl)-4-oxo-8-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3,5-difluorophenyl)-5-fluoro-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propylcarbamate;

(S)-tert-butyl1-(3-(3,5-difluorophenyl)-5-fluoro-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)propylcarbamate;

(S)-tert-butyl1-(8-chloro-3-(3,5-difluorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3-(difluoromethyl)-5-fluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3,5-difluorophenyl)-8-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3-cyanophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(8-methyl-4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-fluoro-4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(8-(difluoromethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(8-(difluoromethyl)-3-phenyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(8-methyl-3-phenyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-fluoro-3-phenyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(8-fluoro-3-phenyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-chloro-3-(3-fluorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-chloro-3-(3-chlorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-chloro-8-methyl-3-phenyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-fluoro-8-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(8-fluoro-5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-(difluoromethyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl3-(3-cyanophenyl)-1-(5-(difluoromethyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-3-(2-(1-aminoethyl)-8-fluoro-5-methyl-4-oxoquinazolin-3(4H)-yl)benzonitrile;

(S)-tert-butyl1-(3-(3-cyanophenyl)-8-fluoro-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-chloro-3-(3,5-dichlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3,5-dichlorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(8-chloro-3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3-chlorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-cyano-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-chloro-3-(3-chloro-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3-chloro-5-fluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-chloro-3-(3-fluoro-5-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-fluoro-3-(5-trifluoromethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propylcarbamate;

(S)-tert-butyl1-(5-chloro-3-(5-trifluoromethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3-cyano-5-fluorophenyl)-5-fluoro-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3-cyanophenyl)-5-fluoro-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3-(difluoromethyl)-5-fluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propylcarbamate;

(S)-tert-butyl1-(5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propylcarbamate;

(S)-tert-butyl1-(3-(3-(difluoromethyl)-5-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-(difluoromethyl)-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3-(difluoromethyl)phenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3,5-difluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-(methylsulfonyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl(1-(3-(3,5-difluorophenyl)-8-iodo-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl1-(8-chloro-3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propylcarbamate;

(S)-tert-butyl1-(3-(3,5-difluorophenyl)-8-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-chloro-3-(3-(difluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-chloro-3-(3-isopropylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-chloro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-carbamoyl-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-carbamoyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-methoxy-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate.

(S)-tert-butyl1-(5-cyano-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-cyano-3-(3-cyano-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3-chloro-5-(difluoromethyl)phenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-chloro-3-(3-chloro-5-(difluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3-(difluoromethyl)phenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3,5-bis(difluoromethyl)phenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3,5-bis(difluoromethyl)phenyl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate.

(S)-tert-butyl1-(5-chloro-3-(3-(difluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(3-(3-(difluoromethyl)phenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-tert-butyl1-(5-bromo-4-oxo-3-(3-fluorophenyl)-3,4-dihydroquinazolin-2-yl)ethylcarbamate;

(S)-2-(1-amino-3,3,3-trifluoropropyl)-3-phenyl-6-fluoroquinazolin-4(3H)-one;

(S)-2-(1-amino-3,3,3-trifluoropropyl)-3-(3,5-difluorophenyl)-6-fluoroquinazolin-4(3H)-one;

(R)-tert-butyl(1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methoxyethyl)carbamate;

(S)-tert-butyl(1-(3-(3,5-bis(difluoromethyl)phenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(3-(3,5-bis(difluoromethyl)phenyl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-cyano-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(3,5-difluorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(3-(2-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(3-(3-cyanophenyl)-5,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)carbamate;

(S)-tert-butyl(1-(5,8-difluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)carbamate;

(S)-tert-butyl(1-(5,8-difluoro-3-phenyl-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)carbamate;

(S)-tert-butyl(1-(3-(3-cyanophenyl)-5,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5,8-difluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(3-(2,6-difluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(2,6-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(6-fluoro-3-(3-fluorophenyl)-8-iodo-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(3-(3-fluorophenyl)-8-iodo-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-8-iodoquinazolin-4(3H)-one;

(S)-tert-butyl(1-(6-fluoro-3-phenyl-8-iodo-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(8-methoxy-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(6-iodo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(3-(3-(difluoromethyl)phenyl)-8-iodo-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(3-(3,5-difluorophenyl)-6-fluoro-8-iodo-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methylbutyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylbutyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-3,3,3-trifluoropropyl)carbamate;

(S)-tert-butyl(1-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-3,3,3-trifluoropropyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(3-cyanophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methylbutyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methylbutyl)carbamate;

(S)-tert-butyl(1-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)butyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(3-cyanophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(6-fluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)carbamate;

(S)-tert-butyl(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(3-cyanophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(3-methoxy-4-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(5-methoxy-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(4-fluoro-3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(5-(difluoromethyl)-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(3-(difluoromethyl)-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(3-(difluoromethyl)-5-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(2,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(3-fluoro-5-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(3-fluoro-5-(trifluoromethoxy)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-2-methylpropyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylpropyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(3-fluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(3,5-difluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(5-fluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(2,3-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(4-fluoro-2,3-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(3,4-difluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-chloro-3-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;and

(S)-tert-butyl(1-(5-chloro-3-(3-fluoro-5-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate.

Example 1b Preparation of Compound of Formula 1b

A. Preparation of a Compound of Formula (1b) in which n is 1, R¹ iscyano, m is 0, and R³ is methyl.

(S)-tert-butyl(1-(5-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate(500 mg, 1.13 mmol), zinc cyanide (166 mg, 1.41 mmol), andtetrakis(triphenylphosphine)Pd(0) (124 mg, 0.11 mmol) were combined inNMP (5 mL). The mixture was degassed under Ar and heated to 90° C.overnight. The reaction was poured into EtOAc, washed with water (3×),and purified by flash chromatography (40 g silica, 0-50% EtOAc/hexanes)to give (S)-tert-butyl(1-(5-cyano-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate asa white solid. ES/MS 391.2 (M+H⁺).

B. Preparation of a Compound of Formula (2), varying n, m, R¹, R², andR³, with one R¹═CN.

(S)-tert-butyl(1-(5-cyano-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;

(S)-tert-butyl(1-(5-cyano-8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;and

(S)-tert-butyl(1-(5-cyano-3-(3,5-difluorophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate.

Example 1c Preparation of a Compound of Formula (1c)

A. Preparation of a Compound of Formula (1c) in which n is 1, R¹ iscarboxamide, m is 0, and R³ is methyl.

To a solution of (S)-tert-butyl(1-(5-cyano-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate(105 mg, 0.269 mmol) in THF/H₂O (1 mL each) was added Ghaffar'scatalyst. The mixture was heated to 80° C. overnight. Purification byflash chromatography (25 g silica, 0-100% EtOAc/DCM) provided(S)-tert-butyl(1-(5-carbamoyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamateas a white solid. ES/MS 409.1 (M+H⁺).

Example 2 Preparation of a Compound of Formula (2)

A. Preparation of a Compound of Formula (2) in which n is 1, R¹ isChloro, m is 0, and R³ is Methyl.

Trifluoroacetic acid (3 mL) was added to a solution of (5)-tert-butyl1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate (1g, 2.5 mmol) in dichloromethane (3 mL). The resultant was stirred atroom temperature for 3 hours. The solvents was removed in vacuuo toafford (S)-2-(1-aminoethyl)-5-chloro-3-phenylquinazolin-4(3H)-one2,2,2-trifluoroacetic acid salt. ES/MS m/z=300.1 (M+H⁺).

B. Preparation of a Compound of Formula (2), Varying R¹, R², and R³

Following the procedure described in Example 2A and Reaction Scheme I,but varying the R¹, R², and R³ substituents, other compounds of formula(2) were prepared including:

(S)-2-(1-aminoethyl)-8-fluoro-3-phenylquinazolin-4(3H)-one, ES/MSm/z=284.1 (M+H⁺);

(S)-2-(1-aminoethyl)-5,8-dichloro-3-phenylquinazolin-4(3H)-one, ES/MSm/z=334.1 (M+H⁺);

(S)-2-(1-aminoethyl)-5-chloro-8-fluoro-3-phenylquinazolin-4(3H)-one,ES/MS m/z=318.1 (M+H⁺);

(S)-2-(1-aminoethyl)-8-chloro-3-phenylquinazolin-4(3H)-one, ES/MSm/z=300.1 (M+H⁺);

(S)-2-(1-aminoethyl)-5,8-difluoro-3-phenylquinazolin-4(3H)-one, ES/MSm/z=302.1 (M+H⁺);

(S)-2-(1-aminoethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminopropyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminopropyl)-5-fluoro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3-fluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-6-fluoroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-phenyl-6-fluoroquinazolin-4(3H)-one;

(S)-3-(2-(1-aminoethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzonitrile;

(S)-3-(2-(1-aminoethyl)-6-floro-4-oxoquinazolin-3(4H)-yl)benzonitrile;

(S)-2-(1-aminoethyl)-3-(3-chlorophenyl)-6-fluoroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-8-fluoroquinazolin-4(3H)-one;

(S)-2-(1-aminopropyl)-3-(3,5-difluorophenyl)-8-fluoroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-5-methylquinazolin-4(3H)-one;

(S)-2-(1-aminopropyl)-3-(3,5-difluorophenyl)-5-methylquinazolin-4(3H)-one;

(S)-2-(1-aminopropyl)-3-(3,5-difluorophenyl)-8-methylquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-8-methylquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5,8-dichloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-5-(2-(1-aminoethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)isophthalonitrile;

(S)-3-(2-(1-aminoethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)-5-fluorobenzonitrile;

(S)-2-(1-aminoethyl)-5,8-difluoro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3,5-difluorophenyl)-8-methylquinazolin-4(3H)-one;

(S)-3-(2-(1-aminoethyl)-5-methyl-4-oxoquinazolin-3(4H)-yl)-5-fluorobenzonitrile;

(S)-2-(1-aminoethyl)-5-methyl-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-8-fluoro-5-methylquinazolin-4(3H)-one

(S)-2-(1-aminoethyl)-5-chloro-3-(3,5-dimethoxyphenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-6,7-difluoro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-8-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminopropyl)-8-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-(difluoromethyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminopropyl)-5-(difluoromethyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminopropyl)-3-(3,5-difluorophenyl)-6-fluoroquinazolin-4(3H)-one;

(S)-2-(1-aminopropyl)-3-(3,5-difluorophenyl)-5,8-difluoroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminopropyl)-3-(3,5-difluorophenyl)-5,6-difluoroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-5,6-difluoroquinazolin-4(3H)-one;

(S)-3-(2-(1-aminoethyl)-5-chloro-8-fluoro-4-oxoquinazolin-3(4H)-yl)-5-fluorobenzonitrile;

(S)-2-(1-aminopropyl)-3-(3,5-difluorophenyl)-6,8-difluoroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-6,8-difluoroquinazolin-4(3H)-one;

(S)-3-(2-(1-aminoethyl)-5-fluoro-4-oxoquinazolin-3(4H)-yl)-5-fluorobenzonitrile;

(S)-2-(1-aminoethyl)-5-fluoro-3-(3-fluoro-5-(trifluoromethyl)phenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-5-fluoro-8-methylquinazolin-4(3H)-one;

(S)-2-(1-aminopropyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminopropyl)-3-(3,5-difluorophenyl)-5-fluoro-8-methylquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-8-chloro-3-(3,5-difluorophenyl)-6-fluoroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3-(difluoromethyl)-5-fluorophenyl)-5-fluoroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-8-methoxyquinazolin-4(3H)-one;

(S)-3-(2-(1-aminoethyl)-5-fluoro-4-oxoquinazolin-3(4H)-yl)benzonitrile;

(S)-2-(1-aminoethyl)-8-methyl-3-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-fluoro-3-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-8-(difluoromethyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-8-(difluoromethyl)-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-8-methyl-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-8-fluoro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3-chlorophenyl)-8-methylquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-8-methyl-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-8-fluoro-5-methyl-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-fluoro-8-methyl-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-(difluoromethyl)-3-phenylquinazolin-4(3H)-one;

(S)-3-(2-(1-aminoethyl)-5-(difluoromethyl)-4-oxoquinazolin-3(4H)-yl)benzonitrile;

(S)-3-(2-(1-aminoethyl)-8-fluoro-5-methyl-4-oxoquinazolin-3(4H)-yl)benzonitrile;

(S)-2-(1-aminoethyl)-3-(3,5-dichlorophenyl)-5-fluoro-quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-8-chloro-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3-chlorophenyl)-8-methylquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carbonitrile;

(S)-2-(1-aminoethyl)-5-chloro-3-(3-chloro-5-fluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3-chloro-5-fluorophenyl)-5-fluoroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3-fluoro-5-(trifluoromethyl)phenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminopropyl)-5-fluoro-3-(5-trifluoromethylphenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-fluoro-3-(5-trifluoromethylphenyl)quinazolin-4(3H)-one;

(S)-3-(2-(1-aminoethyl)-5-fluoro-8-methyl-4-oxoquinazolin-3(4H)-yl)-5-fluorobenzonitrile;

(S)-3-(2-(1-aminoethyl)-5-fluoro-8-methyl-4-oxoquinazolin-3(4H)-yl)benzonitrile;

(S)-2-(1-aminopropyl)-3-(3-(difluoromethyl)-5-fluorophenyl)-5-fluoroquinazolin-4(3H)-one;

(S)-2-(1-aminopropyl)-5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3-(difluoromethyl)-5-fluorophenyl)-5-(methylsulfonyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-(difluoromethyl)-3-(3-(difluoromethyl)-5-fluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3-(difluoromethyl)phenyl)-5-fluoroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-5-(methylsulfonyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-(methylsulfonyl)-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-aminopropyl)-8-chloro-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-8-ethylquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3-(difluoromethyl)phenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3-isopropylphenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3-fluorophenyl)quinazolin-4(3H)-one.

(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazoline-5-carboxamide;

(S)-2-(1-aminoethyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carboxamide;

(S)-2-(1-aminoethyl)-5-methoxy-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazoline-5-carbonitrile;

(S)-2-(1-aminoethyl)-3-(3-cyano-5-fluorophenyl)-4-oxo-3,4-dihydroquinazoline-5-carbonitrile;

(S)-2-(1-aminoethyl)-3-(3-chloro-5-(difluoromethyl)phenyl)-5-fluoroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3-chloro-5-(difluoromethyl)phenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3-(difluoromethyl)phenyl)-5-(methylsulfonyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3-fluorophenyl)-5-(methylsulfonyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3,5-bis(difluoromethyl)phenyl)-5-fluoroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3,5-bis(difluoromethyl)phenyl)-5-chloroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3-(difluoromethyl)phenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3-(difluoromethyl)phenyl)-5-fluoroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-8-carbonitrile;

(S)-2-(1-aminoethyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carbonitrile;

(S)-2-(1-aminoethyl)-4-oxo-3-(3-fluorophenyl)-3,4-dihydroquinazoline-5-carbonitrile;

(S)-2-(1-aminoethyl)-8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carbonitrile;

(S)-2-(1-aminoethyl)-4-oxo-3-(3,5-difluorophenyl)-3,4-dihydroquinazoline-5-carbonitrile;

(S)-2-(1-aminoethyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carboxamide;

(S)-2-(1-aminoethyl)-5-bromo-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-bromo-3-(3-fluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-amino-3,3,3-trifluoropropyl)-3-phenyl-6-fluoroquinazolin-4(3H)-one

(S)-2-(1-amino-3,3,3-trifluoropropyl)-3-(3,5-difluorophenyl)-6-fluoroquinazolin-4(3H)-one;

(R)-2-(1-amino-2-methoxyethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3,5-bis(difluoromethyl)phenyl)-5-fluoroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3,5-bis(difluoromethyl)phenyl)-5-chloroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinazoline-5-carbonitrile;

(S)-2-(1-aminoethyl)-5-chloro-3-(3,5-difluorophenyl)-6-fluoroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)-6-fluoroquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(2-fluorophenyl)-5-(methylsulfonyl)quinazolin-4(3H)-one;

(S)-3-(2-(1-aminopropyl)-5,8-difluoro-4-oxoquinazolin-3(4H)-yl)benzonitrile;

(S)-2-(1-aminopropyl)-5,8-difluoro-3-(3-fluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminopropyl)-5,8-difluoro-3-phenylquinazolin-4(3H)-one;

(S)-3-(2-(1-aminoethyl)-5,8-difluoro-4-oxoquinazolin-3(4H)-yl)benzonitrile;

(S)-2-(1-aminoethyl)-5,8-difluoro-3-(3-fluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(2,6-difluorophenyl)-5-(methylsulfonyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(2,6-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-6-fluoro-3-(3-fluorophenyl)-8-iodoquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3-fluorophenyl)-8-iodoquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-6-fluoro-3-phenyl-8-iodoquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-8-methoxy-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-6-iodo-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3-(difluoromethyl)phenyl)-8-iodoquinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-6-fluoro-8-iodoquinazolin-4(3H)-one;

(S)-2-(1-amino-3-methylbutyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;(S)-2-(1-amino-2-methylbutyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-amino-3,3,3-trifluoropropyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-amino-3,3,3-trifluoropropyl)-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one;

(S)-3-(2-(1-amino-3-methylbutyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzonitrile;

(S)-2-(1-amino-3-methylbutyl)-5-chloro-3-(3-fluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminobutyl)-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one;

(S)-3-(2-(1-aminoethyl)-5-chloro-6-fluoro-4-oxoquinazolin-3(4H)-yl)benzonitrile;

(S)-2-(1-aminopropyl)-6-fluoro-3-(3-fluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminopropyl)-5-fluoro-3-(3-fluorophenyl)quinazolin-4(3H)-one;

(S)-3-(2-(1-aminoethyl)-5-chloro-8-fluoro-4-oxoquinazolin-3(4H)-yl)benzonitrile;

(S)-2-(1-aminoethyl)-5-fluoro-3-(3-fluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3-methoxy-4-methylphenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3-methoxyphenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(5-methoxy-2-methylphenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(4-fluoro-3-methoxyphenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(5-(difluoromethyl)-2-methylphenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3-(difluoromethyl)-2-methylphenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3-(difluoromethyl)-5-methoxyphenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(2,5-dimethylphenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3-fluoro-5-methoxyphenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3-fluoro-5-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one;

(S)-2-(1-amino-2-methylpropyl)-5-chloro-3-phenylquinazolin-4(3H)-one;

(S)-2-(1-amino-2-methylpropyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3-fluoro-2-methylphenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3,5-difluoro-2-methylphenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(5-fluoro-2-methylphenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(2,3-dimethylphenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(4-fluoro-2,3-dimethylphenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3,4-difluoro-2-methylphenyl)quinazolin-4(3H)-one;

(S)-2-(1-aminoethyl)-5-chloro-3-(3-methoxyphenyl)quinazolin-4(3H)-one;and

(S)-2-(1-aminoethyl)-5-chloro-3-(3-fluoro-5-methoxyphenyl)quinazolin-4(3H)-one.

Example 3 Preparation of a Compound of Formula (3)

A. Preparation of a Compound of Formula (3) in which R⁴ is CN and X isCl (2,4-Diamino-6-Chloropyrimidine-5-Carbonitrile)

Ammonium hydroxide (20 mL) was added to a solution of2,4,6-trichloropyrimidine-5-carbonitrile (5.0 g, 24 mmol) in dioxane (20mL) at room temperature. The solution was warmed to 50° C. and stirredfor 3 hrs. The reaction mixture was cooled to 10° C. and water (50 mL)was added. The resulting solid was filtered, washed with water, anddried under high vacuum to afford the compound depicted above as a whitesolid (4.5 g)¹³H NMR (100 MHz, DMSO) 164.8, 162.6, 161.9, 115.8, 77.6.ES/MS m/z=169.9 (M+H)⁺.

B. Preparation of a Compound of Formula (3), Varying R⁴ and X

5-chloro-6-fluoropyrimidine-2,4-diamine;

6-chloro-5-(methylsulfonyl)pyrimidine-2,4-diamine;

6-chloro-5-(trifluoromethyl)pyrimidine-2,4-diamine; and

2,4-diamino-6-chloropyrimidine-5-carboxamide.

Example 4 Preparation of a Compound of Formula (I)

A. Preparation of a Compound of Formula (I) in which n=1, R¹ is Chloro,m=2, Both R² are Fluoro, R³ is Methyl, and R⁴ is Cyano (Compound 1a)

Potassium fluoride (138 mg, 2.38 mmol) was added to a solution of(S)-2-(1-aminoethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(400 mg, 1.19 mmol) and 2,4-diamino-6-chloropyrimidine-5-carbonitrile(201 mg, 1.19 mmol) in diisopropylethylamine (1.0 mL, 6.0 mmol) and DMSO(3 mL). The resultant mixture was heated to 90° C. for 14 hours, afterwhich time the reaction was cooled to room temperature, filtered, andpurified by HPLC eluting with 5%-95% water/acetonitrile (0.1% v/vtrifluoroacetic acid). The appropriate fractions were pooled andlyophilized to afford Compound 1a as a white solid (479 mg). ¹H NMR (400MHz, DMSO) δ 7.78 (t, J=8.0 Hz, 1H), 7.65 (dd, J=8.2, 1.2 Hz, 1H), 7.58(dd, J=7.8, 1.2 Hz, 1H), 7.43 (dm, J=9.2 Hz, 1H), 7.29 (dt, J=9.2, 2.4Hz, 1H), 7.24 (dm, J=11 Hz, 1H), 6.83 (d, J=6.8 Hz, 1H), 6.51 (br s,1H), 6.24 (br s, 1H), 4.82 (dq, J=6.65, 6.65 Hz, 1H), 1.34 (d, J=6.65Hz, 3H). ES/MS 469.1 (M+H⁺).

B. Preparation of a Compound of Formula (I), varying R¹, R², and R³; anda Compound of Formula (J), varying R¹, R², R³ and R⁴

(S)-2,4-diamino-6-((1-(5-hydroxy-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 2a): ¹H NMR (400 MHz, DMSO) δ 11.56 (s, 1H), 7.96-7.78 (br. M,2H), 7.74 (t, J=8.2 Hz, 1H), 7.60-7.36 (m, 5H), 7.17 (dd, J=8.1, 0.9 Hz,1H), 6.92 (dd, J=8.2, 0.9 Hz, 1H), 4.95-4.84 (m, 1H), 1.33 (d, J=6.7 Hz,3H). ES/MS 415.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(8-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 3a): ¹H NMR (400 MHz, DMSO) δ 7.96 (ddd, J=7.9, 1.5, 0.6 Hz,1H), 7.75 (ddd, J=7.4, 1.5, 0.9 Hz, 1H), 7.57-7.41 (m, 6H), 4.96-4.86(m, 1H), 2.62 (s, 3H), 1.33 (d, J=6.6 Hz, 3H). ES/MS 413.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(5-chloro-8-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 4a): ¹H NMR (400 MHz, DMSO) δ 7.68 (dd, J=8.1, 0.8 Hz, 1H),7.58-7.40 (br. M, 4H), 7.39-6.75 (m, 6H), 4.90-4.80 (m, 1H), 2.56 (s,3H), 1.31 (d, J=6.6 Hz, 3H). ES/MS 447.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(5-chloro-3-(3-chlorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 5a): ¹H NMR (400 MHz, DMSO) δ 7.78-7.67 (m, 3H), 7.55-7.40 (m,5H), 4.99-4.84 (m, 1H), 2.60-2.54 (m, 3H), 1.41-1.30 (m, 3H). ES/MS481.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(3-(3-chlorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 6a): ¹H NMR (400 MHz, DMSO) δ 7.97-7.92 (m, 1H), 7.76-7.71 (m,1H), 7.62-7.41 (m, 5H), 6.96-6.79 (m, 1H), 6.59-6.46 (m, 2H), 6.34-6.12(m, 2H), 4.90-4.80 (m, 1H), 2.64-2.58 (m, 3H), 1.37-1.27 (m, 3H). ES/MS447.1 (M+H⁺);

(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carbonitrile(Compound 7a): ¹H NMR (400 MHz, DMSO) δ 8.05 (dd, J=4.8, 3.9 Hz, 1H),7.99-7.95 (m, 2H), 7.62-7.45 (m, 5H), 6.80 (d, J=6.9 Hz, 1H), 6.54 (br.S, 2H), 6.25 (br. S, 2H), 4.79-4.70 (m, 1H), 1.30 (d, J=6.7 Hz, 3H).ES/MS 424.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-chloro-3-(3-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 8a): ¹H NMR (400 MHz, DMSO) δ 7.79 (ddd, J=17.0, 10.3, 3.2 Hz,1H), 7.67 (ddd, J=13.3, 8.2, 1.2 Hz, 1H), 7.60 (ddd, J=7.8, 4.6, 1.2 Hz,1H), 7.53-7.44 (m, 2H), 7.40 (qd, J=6.6, 4.6 Hz, 1H), 5.00-4.83 (m, 1H),1.36 (dd, J=9.4, 6.7 Hz, 2H). ES/MS 467.3 (M+H⁺);

(S)-2,4-diamino-6-(1-(6-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 9a): ¹H NMR (400 MHz, DMSO) δ 7.93 (s, 1H), 7.86-7.64 (m, 5H),7.50 (dt, J=10.0, 4.2 Hz, 2H), 7.46-7.34 (m, 4H), 5.00-4.85 (m, 1H),1.34 (d, J=6.7 Hz, 3H). ES/MS 417.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 10a): ¹H NMR (400 MHz, DMSO) δ 7.87 (dd, J=13.6, 8.1 Hz, 1H),7.57 (s, 2H), 7.55 (d, J=8.2 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.38-7.19(m, 2H), 7.15 (d, J=8.6 Hz, 1H), 5.11-4.85 (m, 1H), 1.38 (d, J=6.6 Hz,3H). ES/MS 453.3 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrileCompound 11a): ¹H NMR (400 MHz, DMSO) δ 7.88-7.67 (m, 4H), 7.48 (d,J=9.1 Hz, 1H), 7.38-7.18 (m, 2H), 7.12 (d, J=8.4 Hz, 2H), 5.11-4.88 (m,1H), 1.34 (t, J=37.5 Hz, 3H). ES/MS 453.2 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-chloro-3-(3-cyanophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 12a): ¹H NMR (400 MHz, DMSO) δ 8.13 (t, J=1.6 Hz, 1H), 7.93(ddd, J=8.0, 2.0, 1.2 Hz, 1H), 7.88-7.83 (m, 1H), 7.80 (dd, J=9.5, 1.7Hz, 2H), 7.75-7.66 (m, 3H), 7.61 (ddd, J=7.5, 4.3, 3.2 Hz, 1H),7.18-7.08 (m, 1H), 6.77-6.68 (m, 1H), 4.96-4.77 (m, 1H), 1.33 (t, J=16.1Hz, 3H). ES/MS 457.9 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3-cyanophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 13a): ¹H NMR (400 MHz, DMSO) δ 8.14 (t, J=1.7 Hz, 1H), 7.94(d, J=7.9 Hz, 1H), 7.90-7.75 (m, 6H), 7.75-7.65 (m, 1H), 7.60 (t, J=7.9Hz, 1H), 4.99-4.83 (m, 1H), 1.35 (t, J=13.0 Hz, 3H). ES/MS 442.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3-chlorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 14a): ¹H NMR (400 MHz, DMSO) δ 8.14-7.74 (m, 6H), 7.71-7.28(m, 5H), 5.14-4.69 (m, 1H), 1.38 (dd, J=9.0, 6.8 Hz, 3H). ES/MS 451.5(M+H⁺);

(S)-2,4-diamino-6-(1-(5-chloro-3-(3,5-difluorophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 15a): ¹H NMR (400 MHz, DMSO) δ 7.91-7.71 (m, 2H), 7.62 (dd,J=8.8, 4.5 Hz, 2H), 7.46 (d, J=9.0 Hz, 1H), 7.37-7.26 (m, 1H), 7.13 (d,J=9.1 Hz, 1H), 5.05-4.88 (m, 1H), 1.33 (t, J=36.2 Hz, 3H). ES/MS 487.6(M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 16a): ¹H NMR (400 MHz, DMSO) δ 7.95 (d, J=8.0 Hz, 2H),7.86-7.69 (m, 2H), 7.58 (td, J=8.0, 4.7 Hz, 2H), 7.48 (d, J=9.0 Hz, 1H),7.41-7.18 (m, 2H), 7.14 (d, J=9.0 Hz, 1H), 5.09-4.86 (m, 1H), 1.40 (d,J=6.6 Hz, 3H) ES/MS 453.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propylamino)pyrimidine-5-carbonitrile(Compound 17a): ¹H NMR (400 MHz, DMSO) δ 7.95 (dd, J=8.0, 0.9 Hz, 1H),7.86-7.69 (m, 1H), 7.55 (ddd, J=30.0, 16.6, 7.0 Hz, 2H), 7.32 (tt,J=9.3, 2.4 Hz, 1H), 7.17 (d, J=9.1 Hz, 1H), 4.84 (dd, J=12.9, 7.3 Hz,1H), 2.11-1.91 (m, 1H), 1.94-1.62 (m, 1H), 0.81 (t, J=7.3 Hz, 3H). ES/MS467.3 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 18a): ¹H NMR (400 MHz, DMSO) δ 7.92 (s, 1H), 7.80-7.66 (m,1H), 7.61-7.40 (m, 2H), 7.37-7.18 (m, 2H), 7.14 (d, J=9.0 Hz, 1H),5.02-4.80 (m, 1H), 2.82-2.64 (s, 3H), 1.38 (s, 3H). ES/MS 449.2 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)propylamino)pyrimidine-5-carbonitrile(Compound 19a): ¹H NMR (400 MHz, DMSO) δ 7.87 (s, 3H), 7.75-7.66 (m,1H), 7.50 (dd, J=24.2, 8.6 Hz, 3H), 7.38-7.24 (m, 2H), 7.24-7.06 (m,2H), 4.80 (dd, J=13.1, 7.5 Hz, 1H), 2.90-2.57 (m, 3H), 2.11-1.86 (m,1H), 1.77 (dt, J=29.5, 11.4 Hz, 1H), 0.82 (m, 3H). ES/MS 463.2 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-chloro-3-(3-cyano-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 20a): ¹H NMR (400 MHz, DMSO) δ 8.12-7.97 (m, 1H), 7.96-7.76(m, 4H), 7.73 (ddd, J=8.1, 2.4, 1.1 Hz, 1H), 7.67-7.61 (m, 1H),5.08-4.78 (m, 1H), 1.40 (d, J=6.6 Hz, 3H). ES/MS 476.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-5,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 21a): ¹H NMR (400 MHz, DMSO) δ 7.83 (d, J=9.9 Hz, 1H),7.56-7.26 (m, 4H), 7.17 (d, J=9.0 Hz, 1H), 5.13-4.84 (m, 1H), 1.41 (d,J=6.6 Hz, 3H). ES/MS 471.2 (M+H⁺);

(S)-2,4-diamino-6-(1-(8-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 22a): ¹H NMR (400 MHz, DMSO) δ 8.08 (dd, J=16.8, 7.2 Hz, 2H),7.68-7.48 (m, 4H), 7.45 (s, 3H), 5.07-4.84 (m, 1H), 1.38 (d, J=6.5 Hz,3H). ES/MS 432.9 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 23a): ¹H NMR (400 MHz, DMSO) δ 7.92 (s, 1H), 7.80-7.66 (m,1H), 7.61-7.40 (m, 2H), 7.37-7.18 (m, 4H), 7.14 (d, J=9.0 Hz, 1H),5.02-4.80 (m, 1H), 2.82-2.64 (s, 3H), 1.38 (s, 3H). ES/MS 413.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3-cyano-5-fluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 24a): ¹H NMR (400 MHz, DMSO) δ 8.17-7.80 (m, 4H), 7.76 (t,J=7.7 Hz, 1H), 7.66-7.55 (m, 1H), 7.38 (d, J=7.4 Hz, 1H), 5.03-4.81 (m,1H), 2.76 (d, J=14.7 Hz, 3H), 1.42 (t, J=9.7 Hz, 3H). ES/MS 456.3(M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-8-fluoro-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 25a): ¹H NMR (400 MHz, DMSO) δ 7.66 (dd, J=10.0, 8.3 Hz, 4H),7.48 (d, J=9.2 Hz, 1H), 7.40-7.28 (m, 2H), 7.15 (d, J=9.3 Hz, 2H), 6.15(ddd, J=6.4, 5.8, 3.6 Hz, 1H), 5.13-4.84 (m, 1H), 2.68 (d, J=7.0 Hz,3H), 1.41 (d, J=6.6 Hz, 3H). ES/MS 467.2 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propylamino)pyrimidine-5-carbonitrile(Compound 26a): ¹H NMR (400 MHz, DMSO) δ 7.66 (dd, J=10.0, 8.3 Hz, 4H),7.48 (d, J=9.2 Hz, 1H), 7.40-7.28 (m, 2H), 7.15 (d, J=9.3 Hz, 2H), 6.15(ddd, J=6.4, 5.8, 3.6 Hz, 1H), 5.13-4.84 (m, 1H), 2.68 (d, J=7.0 Hz,3H), 1.41 (d, J=6.6 Hz, 3H). ES/MS 467.4 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-5,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propylamino)pyrimidine-5-carbonitrile(Compound 27a): ¹H NMR (400 MHz, DMSO) δ 8.02-7.77 (m, 1H), 7.65-7.25(m, 4H), 7.20 (d, J=9.4 Hz, 1H), 4.80 (dd, J=12.9, 7.5 Hz, 1H),2.08-1.67 (m, 2H), 0.88-0.65 (m, 3H). ES/MS 485.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 28a): ¹H NMR (400 MHz, DMSO) δ 8.32-8.10 (m, 1H), 7.91 (ddd,J=23.8, 12.7, 9.1 Hz, 1H), 7.76 (dd, J=14.1, 6.5 Hz, 1H), 7.68-7.56 (m,1H), 7.50 (d, J=9.2 Hz, 1H), 7.32 (tt, J=9.3, 2.4 Hz, 1H), 7.18 (d,J=9.1 Hz, 1H), 5.08-4.94 (m, 1H), 1.54-1.31 (m, 3H). ES/MS 435.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-5,6-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 29a): ¹H NMR (400 MHz, DMSO) δ 8.01 (dd, J=18.7, 9.1 Hz, 1H),7.63 (dd, J=8.9, 3.5 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.33 (dd, J=10.5,8.2 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 5.04-4.88 (m, 1H), 1.37 (t, J=20.2Hz, 3H). ES/MS 471.2 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-5,6-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propylamino)pyrimidine-5-carbonitrile(Compound 30a): ¹H NMR (400 MHz, DMSO) δ 8.00 (dd, J=18.4, 9.1 Hz, 1H),7.61 (dd, J=8.6, 3.5 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.35 (t, J=9.3 Hz,1H), 7.21 (d, J=8.6 Hz, 1H), 4.78 (d, J=5.6 Hz, 1H), 1.98 (dd, J=13.1,6.5 Hz, 1H), 1.96-1.70 (m, 1H), 0.81 (t, J=7.3 Hz, 3H). ES/MS 485.3(M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3-cyano-5-fluorophenyl)-8-fluoro-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 31a): ¹H NMR (400 MHz, DMSO) δ 8.16-7.84 (m, 2H), 7.76-7.54(m, 2H), 7.38 (s, 2H), 4.97 (m, 1H), 2.68 (s, 3H), 1.41 (d, J=6.5 Hz,3H). ES/MS 474.3 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3-cyano-5-fluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 32a): ¹H NMR (400 MHz, DMSO) δ 8.12-7.77 (m, 3H), 7.63 (dd,J=23.6, 9.0 Hz, 2H), 7.45-7.19 (m, 1H), 5.04-4.62 (m, 1H), 1.39 (d,J=6.5 Hz, 3H). ES/MS 460.4 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-fluoro-3-(3-fluoro-5-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 33a): ¹H NMR (400 MHz, DMSO) δ 8.02-7.85 (m, 1H), 7.77-7.62(m, 1H), 7.65-7.45 (m, 2H), 7.37 (dd, J=18.2, 7.5 Hz, 2H), 5.27-4.66 (m,1H), 1.38 (dd, J=13.9, 6.6 Hz, 3H). ES/MS 503.6 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-4-oxo-8-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 34a): ¹H NMR (400 MHz, DMSO) δ 8.43 (d, J=8.1 Hz, 1H), 8.30(d, J=7.7 Hz, 1H), 7.75 (t, J=7.8 Hz, 2H), 7.54 (d, J=9.9 Hz, 1H), 7.32(t, J=9.3 Hz, 1H), 7.14 (d, J=9.6 Hz, 1H), 6.75 (d, J=8.6 Hz, 4H),6.25-5.95 (m, 1H), 5.24-4.98 (m, 1H), 1.43 (d, J=6.6 Hz, 3H). ES/MS503.3 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-5-fluoro-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 35a): ¹H NMR (400 MHz, DMSO) δ 7.77 (dd, J=8.5, 5.5 Hz, 1H),7.49 (d, J=9.1 Hz, 1H), 7.31 (ddd, J=19.3, 10.1, 7.6 Hz, 2H), 7.19 (d,J=8.6 Hz, 1H), 5.16-4.76 (m, 1H), 2.57 (s, 3H), 1.41 (d, J=6.6 Hz, 3H).ES/MS 467.2 (M+H⁺).

(S)-2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propylamino)pyrimidine-5-carbonitrile(Compound 36a): ¹H NMR (400 MHz, DMSO) δ 8.22-8.07 (m, 1H), 7.99-7.84(m, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.64-7.43 (m, 2H), 7.39-7.25 (m, 1H),7.20 (d, J=8.5 Hz, 1H), 4.83 (dd, J=12.9, 7.4 Hz, 1H), 2.10-1.89 (m,1H), 1.89-1.61 (m, 1H), 0.85-0.69 (m, 3H). ES/MS 449.3 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-5-fluoro-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)propylamino)pyrimidine-5-carbonitrile(Compound 37a): ¹H NMR (400 MHz, DMSO) δ 7.93-7.64 (m, 2H), 7.49 (d,J=9.0 Hz, 1H), 7.36-6.85 (m, 4H), 6.34-5.98 (m, 1H), 4.90 (dd, J=13.5,6.6 Hz, 1H), 2.55 (s, 3H), 2.15-1.93 (m, 1H), 1.77 (dt, J=13.9, 6.9 Hz,1H), 0.84 (t, J=7.2 Hz, 3H). ES/MS 481.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3-cyanophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 38a): ¹H NMR (400 MHz, DMSO) δ 8.13 (s, 1H), 7.99-7.73 (m,3H), 7.70 (d, J=7.8 Hz, 1H), 7.65-7.52 (m, 2H), 7.46-7.22 (m, 2H), 4.87(dd, J=14.3, 7.7 Hz, 1H), 1.36 (d, J=6.5 Hz, 3H). ES/MS 442.4 (M+H⁺);

(S)-2,4-diamino-6-(1-(8-methyl-4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 39a): ¹H NMR (400 MHz, DMSO) δ 8.08 (t, J=25.4 Hz, 1H),8.04-7.82 (m, 2H), 7.85-7.62 (m, 3H), 7.59-7.31 (m, 1H), 5.16-4.76 (m,1H), 2.72-2.59 (m, 3H), 1.53-1.33 (m, 3H). ES/MS 481.2 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-fluoro-4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 40a): ¹H NMR (400 MHz, DMSO) δ 8.08 (s, 1H), 8.02-7.77 (m,3H), 7.76-7.55 (m, 3H), 5.13-4.68 (m, 1H), 1.37 (dd, J=18.9, 6.6 Hz,3H). ES/MS 485.4 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-chloro-3-(3,5-dichlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 41a): ¹H NMR (400 MHz, DMSO) δ 7.90 (s, 1H), 7.86-7.73 (m,4H), 7.73-7.65 (m, 2H), 7.65-7.53 (m, 2H), 7.37 (t, J=1.8 Hz, 1H), 4.95(dd, J=13.7, 6.7 Hz, 1H), 1.37 (d, J=6.6 Hz, 3H). ES/MS 501.5 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3,5-dichlorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 42a): ¹H NMR (400 MHz, DMSO) δ 7.86 (td, J=8.2, 5.6 Hz, 1H),7.77-7.67 (m, 1H), 7.61-7.46 (m, 2H), 7.35 (dd, J=17.2, 6.3 Hz, 2H),5.12-4.72 (m, 1H), 1.37 (d, J=6.6 Hz, 3H). ES/MS 486.3 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-chloro-3-(3-chloro-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 43a): ¹H NMR (400 MHz, DMSO) δ 8.01-7.74 (m, 1H), 7.74-7.54(m, 1H), 7.55-7.18 (m, 4H), 5.06-4.74 (m, 1H), 1.36 (t, J=6.1 Hz, 3H).ES/MS 486.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3-chloro-5-fluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 44a): ¹H NMR (400 MHz, DMSO) δ 7.93 (dd, J=22.1, 13.3 Hz, 1H),7.87-7.74 (m, 1H), 7.69 (ddd, J=14.1, 8.2, 1.2 Hz, 2H), 7.60 (m, 3H),5.09-4.81 (m, 1H), 1.47-1.26 (m, 3H). ES/MS 468.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-chloro-3-(3-fluoro-5-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 45a): ¹H NMR (400 MHz, DMSO) δ 7.93 (dd, J=22.1, 13.3 Hz, 1H),7.87-7.74 (m, 1H), 7.69 (ddd, J=14.1, 8.2, 1.2 Hz, 2H), 7.60 (m, 3H),5.09-4.81 (m, 1H), 1.47-1.26 (m, 3H). ES/MS 518.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-fluoro-4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-2-yl)propylamino)pyrimidine-5-carbonitrile(Compound 46a): ¹H NMR (400 MHz, DMSO) δ 7.95-7.63 (m, 4H), 7.52 (dd,J=24.6, 8.1 Hz, 1H), 7.32 (dd, J=18.9, 10.7 Hz, 2H), 4.92-4.40 (m, 1H),2.14-1.86 (m, 1H), 1.89-1.54 (m, 1H), 0.89-0.45 (m, 3H). ES/MS 498.2(M+H⁺);

(S)-2,4-diamino-6-(1-(5-chloro-4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 47a): ¹H NMR (400 MHz, DMSO) δ 8.01 (d, J=38.7 Hz, 1H),7.91-7.75 (m, 3H), 7.75-7.63 (m, 4H), 7.63-7.52 (m, 2H), 5.02-4.74 (m,1H), 1.43-1.19 (m, 3H). ES/MS 500.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-chloro-3-(3-cyano-5-fluorophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 48a): ¹H NMR (400 MHz, DMSO) δ 8.00 (dd, J=25.2, 16.0 Hz, 1H),7.85 (dd, J=26.3, 17.5 Hz, 2H), 7.73-7.56 (m, 2H), 5.11-4.81 (m, 1H),1.40 (d, J=6.6 Hz, 3H). ES/MS 494.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 49a): ¹H NMR (400 MHz, DMSO) δ 7.78 (t, J=8.0 Hz, 1H), 7.63(dd, J=8.2, 1.2 Hz, 1H), 7.57 (dd, J=7.8, 1.2 Hz, 1H), 7.57-7.45 (m,5H), 6.79 (d, J=7.0 Hz, 1H), 6.55 (br s, 1H), 6.25 (br s, 1H), 4.72 (dq,J=6.45, 6.45 Hz, 1H), 1.29 (d, J=6.8 Hz, 3H). ES/MS 433.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(5,8-dichloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 50a): ¹H NMR (400 MHz, DMSO) δ 7.98 (d, J=8.6 Hz, 1H), 7.58(d, J=8.4 Hz, 1H), 7.55-7.38 (m, 5H), 7.9-6.9 (very broad, 3H), 4.91(dq, J=6.85, 6.85 Hz, 1H), 1.34 (d, J=6.65 Hz, 3H). ES/MS 468.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-chloro-3-(3,5-dimethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 51a): ¹H NMR (400 MHz, DMSO) δ 7.77 (t, J=7.8 Hz, 1H), 7.64(d, J=8.0 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 6.73 (m, 1H), 6.55 (m, 1H),6.47 (m, 1H), 5.03 (m, 1H), 3.73 (s, 3H), 3.68 (s, 3H), 1.37 (d, J=6.6Hz, 3H). ES/MS 493.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-(difluoromethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 52a): ¹H NMR (400 MHz, DMSO) δ 8.04-7.75 (m, 5H), 7.72-7.45(m, 3H), 7.42-7.10 (m, 4H), 5.03-4.97 (m, 1H), 1.40 (d, J=7.7 Hz, 3H).ES/MS 485.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-(difluoromethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propylamino)pyrimidine-5-carbonitrile(Compound 53a): ¹H NMR (400 MHz, DMSO) δ 8.04-7.74 (m, 5H), 7.72-7.37(m, 4H) 7.36-7.05 (m, 3H), 4.87-4.79 (m, 1H), 2.06-1.95 (m, 1H),1.84-1.76 (m, 1H), 0.80 (t, J=7.4 Hz, 3H). ES/MS 499.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3-(difluoromethyl)-5-fluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 54a): ¹H NMR (400 MHz, DMSO) δ 8.05-7.33 (m, 9H), 7.29-6.81(m, 3H), 5.05-4.86 (m, 1H), 1.43-1.34 (m, 3H). ES/MS 485.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 55a): ¹H NMR (400 MHz, DMSO) δ 7.93-7.57 (m, 6H), 7.55-7.30(m, 3H), 7.26-6.92 (m, 3H), 5.05-4.87 (m, 1H), 1.44-1.36 (m, 3H). ES/MS501.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(8-(difluoromethyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 56a): ¹H NMR (400 MHz, DMSO) δ 8.31 (d, J=7.8 Hz, 1H), 8.16(d, J=7.0 Hz, 1H), 7.91-7.05 (m, 12H), 5.03-4.93 (m, 1H), 1.37 (d, J=6.7Hz, 3H). ES/MS 449.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(8-(difluoromethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 57a): ¹H NMR (400 MHz, DMSO) δ 8.33 (d, J=7.4 Hz, 1H), 8.19(d, J=7.4 Hz, 1H), 7.95-7.05 (m, 10H), 5.12-5.03 (m, 1H), 1.44 (d, J=6.7Hz, 3H). ES/MS 485.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 58a): ¹H NMR (400 MHz, DMSO) δ 8.08-7.90 (m, 2H), 7.86-7.70(m, 3H), 7.65-7.50 (m, 4H), 7.47-7.20 (m, 4H), 5.01-4.92 (m, 1H), 1.38(d, J=6.6 Hz, 3H). ES/MS 417.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(5,8-difluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 59a): ¹H NMR (400 MHz, DMSO) δ 7.92-7.72 (m, 2H), 7.70-7.50(m, 4H), 7.48-7.11 (m, 6H), 4.93-4.85 (m, 1H), 1.36 (d, J=6.7 Hz, 3H).ES/MS 435.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(8-fluoro-5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 60a): ¹H NMR (400 MHz, DMSO) δ 7.91 (br s, 1H), 7.78 (br s,2H), 7.63 (t, J=9.0 Hz, 1H), 7.57-7.47 (m, 3H), 7.46-7.37 (m, 3H),7.37-7.24 (m, 2H), 4.95-4.86 (m, 1H), 2.51 (s, 3H), 1.36 (d, J=6.2 Hz,3H). ES/MS 431.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-fluoro-8-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 61a): ¹H NMR (400 MHz, DMSO) δ 7.87-7.60 (m, 4H), 7.58-7.42(m, 6H), 7.40-7.11 (m, 2H), 4.95-4.87 (m, 2H), 2.57 (s, 3H), 1.35 (d,J=6.7 Hz, 3H). ES/MS 431.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-(difluoromethyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 62a): ¹H NMR (400 MHz, DMSO) δ 8.09-7.65 (m, 7H), 7.62-7.13(m, 7H), 4.99-4.90 (m, 1H), 1.38 (d, J=6.7 Hz, 3H). ES/MS 449.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3-cyanophenyl)-5-(difluoromethyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 63a): ¹H NMR (400 MHz, DMSO) δ 8.19-8.01 (m, 3H), 8.00-7.83(m, 6H), 7.81-7.60 (m, 4H), 5.03-4.90 (m, 1H), 1.41 (d, J=6.7 Hz, 3H).ES/MS 474.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3-cyanophenyl)-8-fluoro-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 64a): ¹H NMR (400 MHz, DMSO) δ 8.15-8.13 (m, 1H), 7.97-7.76(m, 4H), 7.75-7.59 (m, 4H), 7.40-7.10 (m, 2H), 4.96-4.85 (m, 1H), 2.68(s, 3H), 1.39 (d, J=6.7 Hz, 3H). ES/MS 456.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3-(difluoromethyl)-5-fluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propylamino)pyrimidine-5-carbonitrile(Compound 65a): ¹H NMR (400 MHz, DMSO) δ 7.92-7.31 (m, 9H), 7.27-6.81(m, 3H), 4.86-4.66 (m, 1H), 2.08-1.86 (m, 1H), 1.85-1.73 (m, 1H),0.85-0.72 (m, 3H). ES/MS 499.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propylamino)pyrimidine-5-carbonitrile(Compound 66a): ¹H NMR (400 MHz, DMSO) δ 7.87-7.40 (m, 9H), 7.32-6.81(m, 3H), 4.86-4.63 (m, 1H), 1.44-1.36 (m, 3H), 2.08-1.86 (m, 1H),1.85-1.73 (m, 1H), 0.85-0.72 (m, 3H). ES/MS 515.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(8-chloro-3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 67a): ¹H NMR (400 MHz, DMSO) δ 8.10 (m, 1H), 7.79, 7.68 (2 bs,3H), 7.48 (m, 1H), 7.42 (m, 1H), 7.35 (m, 1H), 7.13 (m, 1H), 5.06 (m,1H), 1.44 (d, 3H). ES/MS: 487.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-8-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 68a): ¹H NMR (400 MHz, DMSO) δ 7.96 (bs, 1H), 7.75 (bs, 1H),7.70 (m, 1H), 7.49 (m, 3H), 7.33 (m, 1H), 7.16 (m, 1H), 5.02 (m, 1H),3.97 (s, 3H), 2.02 (m, 1H), 1.42 (d, 3H). ES/MS 465.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-6,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile(Compound 69a): ¹H NMR (400 MHz, DMSO) δ 7.97 (m, 1H), 7.73 (m, 1H),7.66 (bs, 2H), 7.51 (m, 1H), 7.35 (m, 1H), 7.18 (m, 1H), 4.85 (m, 1H),2.02 (m, 1H), 1.84 (m, 1H), 0.83 (t, 3H). ES/MS 485.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-6,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 70a): ¹H NMR (400 MHz, DMSO) δ 7.98 (m, 1H), 7.78 (bs, 1H),7.73 (m, 1H), 7.62 (bs, 1H), 7.50 (m, 1H), 7.34 (m, 1H), 7.15 (m, 1H),5.03 (m, 1H), 1.42 (d, 3H). ES/MS calcd. For C₂₁H₁₄F₄N₈O: 470.1. foundm/z=471.1 (M+H⁺).

(S)-2,4-diamino-6-((1-(8-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 71a): ¹H NMR (400 MHz, DMSO) δ 8.11 (m, 2H), 7.83 (bs, 1H),7.67 (bs, 1H), 7.59 (t, 1H), 7.51 (m, 1H), 7.34 (m, 1H), 7.12 (m, 1H),5.09 (m, 1H), 1.45 (d, 3H). ES/MS 469.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(8-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile(Compound 72a): ¹H NMR (400 MHz, DMSO) δ 8.10 (m, 2H), 7.75 (bs, 2H),7.59 (t, 1H), 7.51 (m, 1H), 7.33 (m, 2H), 7.12 (m, 1H), 4.98 (m, 1H),2.08 (m, 1H), 1.83 (m, 1H), 0.89 (t, 3H). ES/MS 483.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(5-chloro-3-(3,5-difluorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 73a): ¹H NMR (400 MHz, DMSO) δ 7.78 (bs, 1H), 7.73 (bs, 1H),7.72 (dd, 1H), 7.49 (m, 2H), 7.36 (m, 1H), 7.18 (m, 1H), 5.03 (m, 1H),2.58 (s, 3H), 1.42 (d, 3H). ES/MS 483.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(5,8-dichloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 74a): ¹H NMR (400 MHz, DMSO) δ 8.04 (d, 1H), 7.76 (bs, 1H),7.66 (bs, 1H), 7.63 (d, 1H), 7.49 (m, 1H), 7.35 (m, 1H), 7.14 (m, 1H),5.05 (m, 1H), 1.43 (d, 3H). ES/MS 503.0 (M+H⁺);

(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 75a): ¹H NMR (400 MHz, DMSO) δ 7.99 (m, 1H), 7.89 (bs, 1H),7.79 (m, 1H), 7.78 (bs, 1H), 7.49 (m, 2H), 7.36 (m, 1H), 7.18 (m, 1H),5.06 (m, 1H), 2.64 (s, 3H), 1.44 (d, 3H). ES/MS 449.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile(Compound 76a): ¹H NMR (400 MHz, DMSO) δ 7.98 (m, 1H), 7.79 (bs, 2H),7.78 (m, 1H), 7.73 (bs, 2H), 7.49 (m, 2H), 7.36 (m, 1H), 7.19 (m, 1H),4.95 (m, 1H), 2.63 (s, 3H), 2.06 (m, 1H), 1.80 (m, 1H), 0.86 (t, 3H).ES/MS 463.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile(Compound 77a): ¹H NMR (400 MHz, DMSO) δ 7.89 (m, 2H), 7.88 (bs, 2H),7.56 (dd, 1H), 7.51 (m, 1H), 7.36 (m, 2H), 7.20 (m, 1H), 4.81 (m, 1H),2.00 (m, 1H), 1.84 (m, 1H), 0.82 (t, 3H). ES/MS calcd. For C₂₂H₁₇F₃N₈O:466.2. found m/z=467.2 (M+H⁺).

(S)-2,4-diamino-6-((1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile(Compound 78a): ¹H NMR (400 MHz, DMSO) δ 7.82 (t, 1H), 7.82 (bs, 2H),7.69 (dd, 1H), 7.63 (dd, 1H), 7.51 (m, 1H), 7.35 (m, 1H), 7.20 (m, 1H),4.80 (m, 1H), 2.00 (m, 1H), 1.83 (m, 1H), 0.81 (t, 3H). ES/MS 483.1(M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-6,7-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 79a): ¹H NMR (400 MHz, DMSO) δ 8.10-8.05 (m, 1H), 7.88-7.84(m, 2H), 7.70 (s, 1H), 7.48-7.46 (d, J=8.8, 1H), 7.33-7.28 (m, 1H),7.12-7.10 (d, J=8.4, 1H), 4.85 (dd, J=13.6, 6.4 Hz, 1H), 1. (d, J=6.4Hz, 3H). ES/MS 471.1 (M+H⁺);

2,4-diamino-6-((3-(3,5-difluorophenyl)-6,7-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methylamino)pyrimidine-5-carbonitrile(Compound 80);

(S)-2,4-diamino-6-(1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 81a): ¹H NMR (400 MHz, DMSO) δ 7.90-7.85 (m, 2H), 7.75 (s,1H), 7.63-7.58 (m, 1H), 7.56 (s, 1H), 7.54-7.52 (m, 2H), 7.46-7.39 (m,3H), 4.89 (dd, J=13.6, 6.4 Hz 1H), 1.38 (d, J=6.4 Hz, 3H). ES/MS 417.2(M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3-cyanophenyl)-5-fluoro-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 82a): ¹H NMR (400 MHz, DMSO) δ 8.15 (s, 1H), 7.97-785 (m, 3H),7.80-7.63 (m, 4H), 7.31-7.25 (m, 1H), 4.96-4.90 (m, 1H), 2.58 (s, 3H),1.40 (t, J=5.2 Hz, 3H). ES/MS 456.2 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3-cyano-5-fluorophenyl)-5-fluoro-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 83a): ¹H NMR (400 MHz, DMSO) δ 8.06-8.00 (m, 2H), 7.96-7.91(m, 2H), 7.84-7.75 (m, 2H), 7.65-7.62 (m, 1H), 4.85 (dd, J=13.0, 6.4 Hz,1H), 2.58 (s, 3H), 1.44 (d, J=6.8 Hz, 3H). ES/MS 474.2 (M+H⁺);

2,4-diamino-6-((8-chloro-3-(3-cyanophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methylamino)pyrimidine-5-carbonitrile(Compound 84);

(S)-2,4-diamino-6-(1-(6-chloro-3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 85a);

(S)-2,4-diamino-6-(1-(6-chloro-3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propylamino)pyrimidine-5-carbonitrile(Compound 86a);

(S)-5-(5-chloro-2-(1-(2,6-diamino-5-cyanopyrimidin-4-ylamino)ethyl)-4-oxoquinazolin-3(4H)-yl)isophthalonitrile(Compound 87a);

(S)-2,4-diamino-6-(1-(3-(3,5-bis(trifluoromethyl)phenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 88a);

(S)-2,4-diamino-6-(1-(8-chloro-3-(3,5-difluorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 89a): ¹H NMR (400 MHz, DMSO) δ 8.19 (dd, J=8.5, 2.9 Hz, 1H),7.85 (dd, J=8.1, 2.9 Hz, 1H), 7.48 (d, J=9.0 Hz, 1H), 7.35-7.28 (m, 1H),7.10 (d, J=8.9 Hz, 1H), 5.11-4.99 (m, 1H), 1.43 (d, J=6.5 Hz, 3H). ES/MS487.5 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carboxamide(Compound 90a): ¹H NMR (400 MHz, DMSO) δ 8.84 (d, J=6.8 Hz, 1H),7.84-7.76 (m, 1H), 7.65 (d, J=1.2 Hz, 1H), 7.62 (dd, J=3.8, 1.2 Hz, 1H),7.60 (d, J=1.2 Hz, 1H), 7.49 (m, 5H), 7.38 (d, J=8.9 Hz, 1H), 4.91-4.68(m, 1H), 1.34 (d, J=6.6 Hz, 3H). (M+H⁺);

(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazoline-5-carboxamide(Compound 91a). ¹H NMR (400 MHz, DMSO) δ 7.85 (dd, J=8.1, 7.4 Hz, 1H),7.72 (dd, J=8.2, 1.2 Hz, 1H), 7.50 (br. S, 1H), 7.43 (br. D, J=9.0 Hz,1H), 7.39 (dd, J=7.3, 1.2 Hz, 1H), 7.95-6.84 (m, 4H), 7.36-7.27 (m, 2H),7.13 (br. D, J=8.5 Hz, 1H), 5.06-4.96 (m, 1H), 1.40 (d, J=6.6 Hz, 3H).ES/MS 478.1 (M+H⁺).

(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carboxamide(Compound 92a). ¹H NMR (400 MHz, DMSO) δ 7.83 (dd, J=8.1, 7.4 Hz, 1H),7.69 (dd, J=8.2, 1.2 Hz, 1H), 8.01-7.04 (br. M, 4H), 7.58-7.39 (m, 5H),7.36 (dd, J=7.3, 1.2 Hz, 1H), 7.27 (br. S, 2H), 4.96-4.83 (m, 1H), 1.33(d, J=6.7 Hz, 3H). ES/MS 442.1 (M+H⁺).

(S)-2,4-diamino-6-(1-(5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carboxamide(Compound 93a): ¹H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 9.65 (s, 1H),7.76-7.67 (m, 3H), 7.60-7.27 (m, 5H), 7.25-6.90 (m, 4H), 4.70-4.63 (m,1H), 1.31 (d, J=7.0 Hz, 3H). ES/MS 519.1 (M+H⁺);

(S)-5-chloro-2-(1-(2,6-diamino-5-(methylsulfonyl)pyrimidin-4-ylamino)ethyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 94a);

(S)-2,4-diamino-6-(1-(5-(methylsulfonyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 95a): ¹H NMR (400 MHz, DMSO) δ 8.33 (dd, J=7.1 and 2.0 Hz,1H), 8.13-8.06 (m, 2H), 8.02-7.62 (m, 4H), 7.59-7.41 (m, 6H), 5.01-4.93(m, 1H), 3.51 (s, 3H), 1.38 (d, J=6.6 Hz, 3H). ES/MS 477.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 96a): ¹H NMR (400 MHz, DMSO) δ 8.37-8.31 (m, 1H), 8.14-8.07(m, 2H), 7.95-7.55 (m, 4H), 7.52 (d, J=8.6 Hz, 1H), 7.40-7.25 (m, 2H),7.15 (d, J=9.0 Hz, 1H), 5.09-5.01 (m, 1H), 3.50 (s, 3H), 1.42 (d, J=6.2Hz, 3H). ES/MS 513.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3-(difluoromethyl)phenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 97a): ¹H NMR (400 MHz, DMSO) δ 8.12-7.45 (m, 9H), 7.42-6.79(m, 4H), 5.00-4.82 (m, 1H), 1.39-1.30 (m, 3H). ES/MS 467.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(3-(3-(difluoromethyl)-5-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 98a): ¹H NMR (400 MHz, DMSO) δ 8.36-8.31 (m, 1H), 8.14-8.07(m, 2H), 8.05-7.55 (m, 4H), 7.50-6.32 (m, 5H), 5.14-4.97 (m, 1H), 3.50(s, 3H), 1.44-1.37 (m, 3H). ES/MS 545.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-(difluoromethyl)-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 99a): ¹H NMR (400 MHz, DMSO) δ 8.07-7.87 (m, 4H), 7.82-7.30(m, 6H), 7.25-6.78 (m, 3H), 5.08-4.93 (m, 1H), 1.43-1.36 (m, 3H). ES/MS517.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-chloro-3-(3-(difluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carboxamide(Compound 100a): ¹H NMR (400 MHz, DMSO) δ 11.10 (br s, 1H), 8.95-8.71(m, 1H), 7.84-7.35 (m, 12H), 7.26-6.83 (m, 1H), 4.77-4.87 (m, 1H),1.32-1.22 (m, 3H). ES/MS 501.1 (M+H⁺);

(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile(Compound 101a): ¹H NMR (400 MHz, DMSO) δ 8.48-8.42 (m, 2H), 7.87 (bs,1H), 7.77-7.73 (m, 1H), 7.74 (bs, 1H), 7.51-7.49 (m, 1H), 7.35-7.29 (m,1H), 7.08-7.05 (m, 1H), 5.15 (m, 1H), 1.48 (d, J=6.4 Hz, 3H). ES/MS460.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(8-chloro-3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile(Compound 102a): ¹H NMR (400 MHz, DMSO) δ 8.11-8.08 (m, 1H), 7.86-7.60(2 bs, 3H), 7.51-7.48 (m, 1H), 7.44-7.39 (m, 1H), 7.36-7.32 (m, 1H),7.13-7.11 (m, 1H), 4.94 (m, 1H), 2.06 (m, 1H), 1.82 (m, 1H), 0.88 (t,3H). ES/MS 501.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-8-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 103a): ¹H NMR (400 MHz, DMSO) δ 8.00 (dd, J=7.6, 1.2 Hz, 1H),7.84 (bs, 1H), 7.78 (dd, J=7.6, 1.6 Hz, 1H), 7.77 (bs 1H), 7.54-7.50 (m,1H), 7.37-7.32 (m, 1H), 7.21-7.18 (m, 1H), 5.06 (m, 1H), 3.10 (m, 2H),1.43 (d, J=6.8 Hz, 3H), 1.30 (t, J=7.2 Hz, 3H). ES/MS 463.2 (M+H⁺);

(S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-phenylquinazolin-4(3H)-one(Compound 104a): ¹H NMR (400 MHz, DMSO) δ 7.80 (t, J=8.0, 1H), 7.72 (bs,1H), 7.69 (d, J=1.2 Hz, 1H), 7.69 (bs, 1H), 7.67 (d, J=1.2 Hz, 1H), 7.61(d, J=1.2 Hz, 1H), 7.59 (d, J=1.2 Hz, 1H), 7.54-7.52 (m, 2H), 7.48 (bs,2H), 7.43-7.40 (m, 3H), 7.31 (bs, 1H), 4.85 (m, 1H), 1.36 (d, J=6.8 Hz,3H). ES/MS 442.1 (M+H⁺);

(S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)propyl)-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one(Compound 105a): ¹H NMR (400 MHz, DMSO) δ 7.92-7.86 (m, 2H), 7.74 (d,J=8 Hz, 1H), 7.58-7.56 (m, 2H), 7.54-7.50 (m, 2H), 7.40-7.31 (m, 2H),7.01-6.93 (m, 1H), 4.77 (m, 1H), 2.02 (m, 1H), 1.84 (m, 1H), 0.84 (t,3H). ES/MS 476.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-chloro-3-(3-(difluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 106a);

(S)-2,4-diamino-6-(1-(5-chloro-3-(3-isopropylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 107a);

(S)-2,4-diamino-6-(1-(5-chloro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 108a);

(S)-2,4-diamino-6-(1-(5-chloro-3-(3-methoxy-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compounds 109a-1 and 109a-2); and

(S)-2,4-diamino-6-(1-(5-chloro-3-(5-fluoro-3-methoxy-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compounds 110a-1 and 110a-2).

(S)-2,4-diamino-6-((1-(5-methoxy-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 111a). ¹H NMR (400 MHz, DMSO) δ 8.05-7.54 (br. M, 4H), 7.75(t, J=8.2 Hz, 1H), 7.53-7.35 (m, 5H), 7.21 (dd, J=8.1, 0.8 Hz, 1H),7.09-7.03 (m, 1H), 4.89-4.77 (m, 1H), 3.82 (s, 3H), 1.31 (d, J=6.6 Hz,1H). ES/MS 429.2 (M+H⁺).

(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazoline-5-carbonitrile(Compound 112a). ¹H NMR (400 MHz, DMSO) δ 8.11 (dd, J=6.5, 2.3 Hz, 1H),8.09-7.99 (m, 2H), 7.95-7.52 (br. M, 4H), 7.52-7.46 (m, 1H), 7.36 (tt,J=9.3, 2.4 Hz, 1H), 7.20 (dd, J=9.1, 0.8 Hz, 1H), 5.03-4.91 (m, 1H),1.40 (d, J=6.6 Hz, 3H). ES/MS 460.1 (M+H⁺).

(S)-3-(3-cyano-5-fluorophenyl)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3,4-dihydroquinazoline-5-carbonitrile(Compound 113a). ¹H NMR (400 MHz, DMSO) δ 8.15-8.10 (m, 1H), 8.10-7.99(m, 3H), 7.98-7.90 (m, 1H), 7.72-7.63 (m, 1H), 7.57-6.81 (br. M, 4H),5.01-4.90 (m, 1H), 1.39 (d, J=6.6 Hz, 3H). ES/MS 467.1 (M+H⁺).

(S)-2,4-diamino-6-((1-(3-(3-chloro-5-(difluoromethyl)phenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 114a): ¹H NMR (400 MHz, DMSO) δ 7.96-7.78 (m, 3H), 7.65-7.50(m, 4H), 7.36-7.31 (m, 2H), 7.21-6.77 (m, 3H), 4.96-4.90 (m, 1H),1.38-1.33 (m, 3H). ES/MS 501.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(5-chloro-3-(3-chloro-5-(difluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 115a): ¹H NMR (400 MHz, DMSO) δ 7.96-7.75 (m, 3H), 7.72-7.64(m, 2H), 7.63-7.50 (m, 4H), 7.21-6.78 (m, 3H), 4.97-4.87 (m, 1H),1.39-1.31 (m, 3H). ES/MS 517.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(3-(3-(difluoromethyl)phenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 116a): ¹H NMR (400 MHz, DMSO) δ 8.36-8.31 (m, 1H), 8.18-8.05(m, 2H), 8.00-7.40 (m, 7H), 7.35-6.83 (m, 3H), 5.08-4.92 (m, 1H),3.51-3.48 (m, 3H), 1.44-1.35 (m, 3H). ES/MS 527.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(3-(3-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 117a): ¹H NMR (400 MHz, DMSO) δ 8.36-8.32 (m, 1H), 8.13-8.05(m, 2H), 8.00-7.65 (m, 3H), 7.63-7.42 (m, 3H), 7.40-7.20 (m, 3H),5.06-4.96 (m, 1H), 3.50 (s, 3H), 1.41 (d, J=6.7 Hz, 3H). ES/MS 495.1(M+H⁺);

(S)-2,4-diamino-6-((1-(3-(3,5-bis(difluoromethyl)phenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 118a): ¹H NMR (400 MHz, DMSO) δ 8.10-7.86 (m, 3H), 7.84-7.66(m, 3H), 7.60 (d, J=8.2 Hz, 1H), 7.45-6.89 (m, 6H), 5.03-4.94 (m, 1H),1.39 (d, J=6.7 Hz, 3H). ES/MS 517.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(3-(3,5-bis(difluoromethyl)phenyl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 119a): ¹H NMR (400 MHz, DMSO) δ 8.08-7.95 (m, 1H), 8.04 (s,1H), 7.90-7.66 (m, 6H), 7.64 (dd, J=5.1 and 1.2 Hz, 1H), 7.33-6.90 (m,4H), 5.02-4.94 (m, 1H), 1.39 (d, J=6.7 Hz, 3H). ES/MS 533.1 (M+H⁺);

(S)-2,4-diamino-6-(1-(5-chloro-3-(3-(difluoroethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 120a). ¹H NMR (400 MHz, DMSO) δ 7.87-7.72 (m, 2H), 7.72-7.64(m, 1H), 7.62-7.46 (m, 4H), 5.04-4.83 (m, 1H), 5.04-4.70 (m, 1H), 1.93(m, 4H), 1.42-1.22 (m, 3H).

(S)-2,4-diamino-6-(1-(3-(3-(difluoromethyl)phenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile(Compound 121a). ¹H NMR (400 MHz, DMSO) δ 7.84 (m, 2H), 7.58 (m, 4H),7.38-7.12 (m, 1H), 5.14-4.61 (m, 2H), 1.93 (dt, J=34.0, 18.8 Hz, 4H),1.34 (dd, J=13.7, 6.5 Hz, 3H). ES/MS 467.1 (M+H⁺).

(S)-2-(1-(2,6-diamino-5-cyanopyrimidin-4-ylamino)ethyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-8-carbonitrile(Compound 122a).

(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carbonitrile(Compound 124a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (dd, J=8.4, 4.5 Hz,1H), 7.93 (dd, J=9.6, 8.4 Hz, 1H), 7.84-7.50 (br. m, 4H), 7.49-7.37 (m,3H), 7.35-6.90 (br. m, 2H), 4.92-4.80 (m, 1H), 1.32 (d, J=6.6 Hz, 3H).ES/MS 442.1 (M+H⁺).

(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazoline-5-carbonitrile(Compound 125a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.14 (dd, J=8.4, 4.5 Hz,1H), 7.97 (dd, J=9.6, 8.5 Hz, 1H), 7.78-6.87 (br. m, 4H), 7.50-7.42 (m,1H), 7.34 (tt, J=9.3, 2.4 Hz, 1H), 7.21-7.13 (m, 1H), 5.01-4.87 (m, 1H),1.37 (d, J=6.5 Hz, 3H). ES/MS 478.1 (M+H⁺).

(S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-8-fluoro-3-phenylquinazolin-4(3H)-one(Compound 127a). ¹H NMR (400 MHz, DMSO-d₆) δ 7.82-7.70 (m, 2H), 7.61(dd, J=8.8, 4.5 Hz, 1H), 7.58-7.48 (m, 4H), 7.44-7.37 (m, 4H), 4.95-4.80(m, 1H), 1.38 (d, J=6.6 Hz, 3H). ES/MS 460.1 (M+H⁺).

(S)-2,4-diamino-6-((1-(5-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 129a). ¹H NMR (400 MHz, DMSO-d₆) δ 7.75 (dd, J=6.6, 2.5 Hz,1H), 7.70-7.59 (m, 2H), 7.57-7.34 (m, 5H), 6.77 (d, J=7.0 Hz, 1H), 6.53(s, 2H), 6.23 (s, 2H), 4.69 (h, J=6.6 Hz, 1H), 1.26 (d, J=6.7 Hz, 3H).ES/MS 477.1 (M+H⁺).

(S)-2,4-diamino-6-((1-(5-bromo-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 130a). ¹H NMR (400 MHz, DMSO-d₆) δ 7.80 (dt, J=5.1, 3.0 Hz,1H), 7.73-7.64 (m, 2H), 7.63-7.48 (m, 1H), 7.48-7.35 (m, 1H), 7.35-7.23(m, 1H), 6.83 (td, J=7.7, 6.8, 4.1 Hz, 1H), 6.54 (s, 2H), 6.25 (d,J=18.2 Hz, 2H), 4.85-4.67 (m, 1H), 1.39-1.27 (m, 3H). ES/MS 495.1(M+H⁺).

(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazoline-5-carbonitrile(Compound 131a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.12-8.05 (m, 1H),8.04-7.95 (m, 2H), 7.64-7.51 (m, 1H), 7.51-7.39 (1, 2H), 7.39-7.26 (m,1H), 6.84 (dd, J=6.8, 4.8 Hz, 1H), 6.55 (s, 2H), 6.26 (d, J=17.5 Hz,2H), 4.87-4.72 (m, 1H), 1.41-1.28 (m, 3H). ES/MS 442.1 (M+H⁺).

(S)-2,4-diamino-6-((3,3,3-trifluoro-1-(6-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile(Compound 132a). ¹H NMR (400 MHz, DMSO-d₆) δ 7.94-6.50 (m, 12H), 5.23(t, J=8.0 Hz, 1H), 3.53 (brs, 2H) 3.19-2.68 (m, 2H). ES/MS 485.2 (M+H)⁺.

(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-3,3,3-trifluoropropyl)amino)pyrimidine-5-carbonitrile(Compound 133a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.37-6.70 (m, 9H),6.58-6.33 (m, 1H), 6.30-6.12 (m, 1H), 5.27 (td, J=7.9, 4.4 Hz, 1H), 3.68(d, J=11.1 Hz, 1H), 3.22-2.87 (m, 2H). ES/MS 521.2 (M+H)⁺.

(R)-2,4-diamino-6-((1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methoxyethyl)amino)pyrimidine-5-carbonitrile(Compound 135a). 1H NMR (400 MHz, DMSO-d6) δ 8.12-7.01 (m, 12H), 5.13(p, J=6.3 Hz, 1H), 3.88 (dt, J=10.6, 5.4 Hz, 1H), 3.66 (dt, J=9.7, 6.0Hz, 1H), 3.21 (s, 3H). ES/MS 499.3 (M+H)⁺;

(S)-2,4-diamino-6-((1-(3-(3,5-bis(difluoromethyl)phenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 136): ¹H NMR (400 MHz, DMSO) δ 8.12-7.96 (m, 3H), 7.90 (td,J=8.2, 5.5 Hz, 1H), 7.85-7.65 (m, 3H), 7.60 (dd, J=8.3, 1.0 Hz, 1H),7.47-6.88 (m, 5H), 4.98 (p, J=6.6 Hz, 1H), 1.39 (d, J=6.6 Hz, 3H). ES/MS517.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(3-(3,5-bis(difluoromethyl)phenyl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 137): ¹H NMR (400 MHz, DMSO) δ 8.11-7.93 (m, 2H), 7.90-7.67(m, 5H), 7.64 (dd, J=7.8, 1.2 Hz, 1H), 7.37-6.88 (m, 3H), 5.02-4.93 (m,1H), 1.39 (d, J=6.6 Hz, 3H). ES/MS 533.1 (M+H⁺);

(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinazoline-5-carbonitrile(Compound 138a): ¹H NMR (400 MHz, DMSO) δ 8.18-7.98 (m, 5H), 7.91-7.31(m, 5H), 7.28-6.80 (m, 2H), 5.10-4.90 (m, 1H), 1.44-1.36 (m, 3H). ES/MS492.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(5-chloro-3-(3,5-difluorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 140a): ¹H NMR (400 MHz, DMSO) δ 8.01-7.72 (m, 7H), 7.49 (dm,J=8.8 Hz, 1H), 7.34 (tt, J=9.4, 2.4 Hz, 1H), 7.19-7.12 (m, 1H), 4.98 (p,J=6.7 Hz, 1H), 1.40 (d, J=6.6 Hz, 3H). ES/MS 487.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 141a): ¹H NMR (400 MHz, DMSO) δ 8.00-7.95 (m, 2H), 7.85-7.51(m, 4H), 7.51-7.38 (m, 3H), 7.26-6.81 (m, 2H), 5.05-4.88 (m, 1H),1.44-1.35 (m, 3H). ES/MS 519.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(3-(2-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 142a-1): ¹H NMR (400 MHz, DMSO) δ 8.36-8.30 (m, 1H), 8.15-8.06(m, 3H), 7.71-7.45 (m, 3H), 7.42-7.25 (m, 3H), 7.23-7.05 (m, 2H),5.30-5.22 (m, 1H), 3.49 (s, 3H), 1.43 (d, J=6.5 Hz, 3H). ES/MS 495.1(M+H⁺);

(S)-2,4-diamino-6-((1-(3-(2-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 142a-2): ¹H NMR (400 MHz, DMSO) δ 8.33 (dt, J=7.4, 1.4 Hz,1H), 8.14-8.04 (m, 3H), 7.87 (br s, 2H), 7.71-7.39 (m, 4H), 7.36-7.10(m, 2H), 5.01-4.94 (m, 1H), 3.49 (s, 3H), 1.35 (d, J=6.5 Hz, 3H). ES/MS495.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(5-chloro-3-(2,6-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 145a): ¹H NMR (400 MHz, DMSO) δ 8.37 (br s, 1H), 7.88 (td,J=8.0, 1.0 Hz, 1H), 7.79-7.61 (m, 4H), 7.50-7.38 (m, 1H), 7.28 (t, J=8.9Hz, 1H), 7.19-7.05 (m, 3H), 5.27-5.18 (m, 1H), 1.43 (d, J=6.5 Hz, 3H).ES/MS 469.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(3-(2,6-difluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 146a): ¹H NMR (400 MHz, DMSO) δ 8.38-8.30 (m, 1H), 8.18-8.13(m, 2H), 7.51-7.41 (m, 2H), 7.30 (t, J=9.0 Hz, 1H), 7.12-7.07 (m, 2H),5.34-5.25 (m, 1H), 3.48 (s, 3H), 1.45 (d, J=6.5 Hz, 3H). ES/MS 513.1(M+H⁺);

(S)-2,4-diamino-6-((1-(5,8-difluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 148a): ¹H NMR (400 MHz, DMSO) δ 7.93-7.61 (m, 5H), 7.57-7.41(m, 2H), 7.41-7.29 (m, 2H), 7.27-7.20 (m, 2H), 4.96-4.82 (m, 1H),1.38-1.32 (d, J=6.5 Hz, 3H). ES/MS 453.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(3-(3-cyanophenyl)-5,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 149a): ¹H NMR (400 MHz, DMSO) δ 8.11-8.08 (m, 1H), 7.91 (ddd,J=8.0, 2.0, 1.2 Hz, 1H), 7.87-7.74 (m, 4H), 7.73-7.66 (m, 2H), 7.62-7.56(m, 1H), 7.40-7.33 (m, 2H), 4.90-4.80 (m, 1H), 1.34 (d, J=6.5 Hz, 3H).ES/MS 460.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(5,8-difluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile(Compound 150a): ¹H NMR (400 MHz, DMSO) δ 7.75 (td, J=9.5, 4.2 Hz, 1H),7.68-7.35 (m, 7H), 7.32 (ddd, J=10.6, 9.1, 3.6 Hz, 1H), 7.11 (br s, 3H),4.68 (td, J=7.7, 4.5 Hz, 1H), 1.90-1.81 (m, 1H), 1.80-1.69 (m, 1H), 0.66(t, J=7.3 Hz, 3H). ES/MS 449.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(5,8-difluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile(Compound 151a): ¹H NMR (400 MHz, DMSO) δ 7.81-7.72 (m, 2H), 7.60-7.40(m, 4H), 7.40-7.19 (m, 5H), 4.75-4.64 (m, 1H), 1.96-1.82 (m, 1H),1.83-1.70 (m, 1H), 0.72 (m, 3H). ES/MS 467.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(3-(3-cyanophenyl)-5,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile(Compound 152): ¹H NMR (400 MHz, DMSO) δ 8.11 (t, J=1.8 Hz, 1H),7.94-7.58 (m, 5H), 7.50-7.20 (m, 4H), 4.70-4.62 (m, 2H), 1.95-1.86 (m,1H), 1.82-1.73 (m, 1H), 0.79-0.69 (m, 3H). ES/MS 474.1 (M+H⁺);

(S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(3-fluorophenyl)-5-(methylsulfonyl)quinazolin-4(3H)-one(Compound 153a): ¹H NMR (400 MHz, DMSO) δ 8.37-8.32 (m, 1H), 8.13-8.09(m, 2H), 7.75 (d, J=7.1 Hz, 1H), 7.64-7.32 (m, 6H), 7.32-7.20 (m, 2H),5.04-4.95 (m, 1H), 3.51 (s, 3H), 1.45-1.41 (m, 3H). ES/MS 504.1 (M+H⁺);(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-8-iodo-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;

(S)-2,4-diamino-6-((1-(8-iodo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;

(S)-2,4-diamino-6-((1-(6-fluoro-3-(3-fluorophenyl)-8-iodo-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;

(S)-2,4-diamino-6-((1-(6-fluoro-3-phenyl-8-iodo-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;

(S)-2,4-diamino-6-((1-(6-iodo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;

(S)-2,4-diamino-6-((1-(3-(3-(difluoromethyl)phenyl)-8-iodo-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;

(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-6-fluoro-8-iodo-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methylbutyl)amino)pyrimidine-5-carbonitrile(Compound 163a): ¹H NMR (400 MHz, DMSO) δ 7.98 (t, J=6.4 Hz, 1H), 7.75(bs, 1H), 7.63 (dd, J=1.2, 8.0 Hz, 1H), 7.61 (dd, J=1.2, 8.0 Hz, 1H),7.56-7.52 (m, 1H), 7.46-7.40 (m, 2H), 4.78 (m, 1H), 1.82 (m, 1H), 1.64(m, 1H), 1.52 (m, 1H), 0.82 (d, J=6.8 Hz, 3H), 0.50 (d, J=6.4 Hz, 3H).ES/MS 511.2 (M+H⁺);

2,4-diamino-6-(((1S,2S)-1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylbutyl)amino)pyrimidine-5-carbonitrile(Compound 164a): ¹H NMR (400 MHz, DMSO) δ 7.98 (bs, 1H), 7.89 (t, J=8.0Hz, 1H), 7.77 (dd, J=1.2, 8.0 Hz, 1H), 7.70 (dd, J=1.2, 7.6 Hz, 1H),7.51-7.48 (m, 1H), 7.39-7.33 (m, 1H), 7.13-7.10 (m, 1H), 4.91 (m, 1H),2.28 (m, 1H), 1.56 (m, 1H), 1.02 (m, 1H), 0.95-0.82 (m, 6H). ES/MS 511.2(M+H⁺);

(S)-2,4-diamino-6-((1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-3,3,3-trifluoropropyl)amino)pyrimidine-5-carbonitrile(Compound 165a): ¹H NMR (400 MHz, DMSO) δ 7.89 (bs, 1H), 7.83 (t, J=8.0Hz, 1H), 7.70 (dd, J=1.2, 8.0 Hz, 1H), 7.65 (dd, J=1.2, 8.0 Hz, 1H),7.51-7.48 (m, 1H), 7.39-7.34 (m, 1H), 7.31-7.29 (m, 1H), 5.22 (m, 1H),3.10-3.00 (m, 2H). ES/MS 537.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-3,3,3-trifluoropropyl)amino)pyrimidine-5-carbonitrile(Compound 166a): ¹H NMR (400 MHz, DMSO) δ 7.96 (bs, 1H), 7.90 (ddd, 1H),7.58 (d, J=8.0 Hz, 1H), 7.50 (m, 1H), 7.42-7.34 (m, 2H), 7.29 (m, 1H),5.24 (m, 1H), 3.17-3.02 (m, 2H). ES/MS 521.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(5-chloro-3-(3-cyanophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methylbutyl)amino)pyrimidine-5-carbonitrile(Compound 167a): ¹H NMR (400 MHz, DMSO) δ 8.22 (t, J=1.6 Hz, 1H), 8.08(t, J=1.6 Hz, 1H), 8.02-7.93 (m, 3H), 7.84-7.77 (m, 4H), 7.66-7.59 (m,5H), 4.70 (m, 2H), 1.80 (m, 2H), 1.47 (m, 4H), 0.79 (m, 4H), 0.44 (d,J=6.4 Hz, 3H), 0.32 (d, J=6.0 Hz, 3H). ES/MS 500.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(5-chloro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methylbutyl)amino)pyrimidine-5-carbonitrile(Compound 168a): ¹H NMR (400 MHz, DMSO) δ 7.80-7.76 (m, 1H), 7.68-7.51(m, 5H), 7.45-7.36 (m, 1H), 4.70 (m, 1H), 1.81 (m, 1.5H), 1.50 (m, 4H),1.26 (m, 0.5H), 0.79 (m, 2H), 0.44 (d, J=6.0 Hz, 1H), 0.32 (d, J=6.0 Hz,1H). ES/MS 493.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)butyl)amino)pyrimidine-5-carbonitrile(Compound 175a). ¹H NMR (400 MHz, DMSO-d₆) δ 7.86 (td, J=8.2, 5.4 Hz,1H), 7.66 (s, 1H), 7.52 (t, J=8.7 Hz, 1H), 7.43-7.03 (m, 3H), 4.81 (q,J=6.9 Hz, 1H), 1.83 (q, J=7.5 Hz, 2H), 1.20 (ddt, J=43.6, 13.8, 6.8 Hz,2H), 0.70 (t, J=7.3 Hz, 3H). ES/MS 481.3 (M+H⁺).

(S)-2,4-diamino-6-((1-(5-chloro-3-(3-cyanophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 176a), ¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (t, J=1.9 Hz, 1H),8.06-7.80 (m, 3H), 7.82-7.50 (m, 3H), 6.99-6.64 (m, 1H), 6.49 (d, J=5.9Hz, 1H), 6.21 (d, J=17.0 Hz, 1H), 4.73 (h, J=6.6 Hz, 1H), 1.29 (d, J=6.6Hz, 3H). ES/MS 476.9 (M+H⁺).

(S)-2,4-diamino-6-((1-(6-fluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile(Compound 178a). ¹H NMR (400 MHz, DMSO-d₆) δ 7.87-7.64 (m, 2H), 7.55(tdd, J=10.1, 5.0, 2.4 Hz, 1H), 7.48-7.15 (m, 2H), 6.67 (dd, J=17.8, 7.5Hz, 1H), 6.53 (d, J=4.8 Hz, 2H), 6.20 (s, 2H), 4.69-4.46 (m, 1H),1.92-1.58 (m, 2H), 0.67 (dt, J=10.0, 7.3 Hz, 3H). ES/MS 449.3 (M+H⁺).

(S)-2,4-diamino-6-((1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile(Compound 179a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.05-7.57 (m, 3H),7.61-7.39 (m, 3H), 7.39-6.85 (m, 4H), 4.71 (tt, J=12.7, 5.9 Hz, 1H),2.04-1.63 (m, 2H), 0.84-0.52 (m, 3H). ES/MS 449.4 (M+H⁺).

(S)-2,4-diamino-6-((1-(5-chloro-3-(3-cyanophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 181a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (t, J=1.7 Hz, 1H),7.98-7.45 (m, 10H), 4.97-4.69 (m, 1H), 1.34 (d, J=6.5 Hz, 3H). ES/MS476.7 (M+H⁺).

(S)-2,4-diamino-6-((1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 182a): ¹H NMR (400 MHz, DMSO-d₆) δ 7.85 (tdd, J=8.2, 5.5, 1.0Hz, 2H), 7.73 (bs, 2H), 7.58-7.18 (m, 5H), 4.89 (dt, J=11.5, 6.7 Hz,1H), 1.34 (dd, J=6.6, 2.6 Hz, 3H). ES/MS 435.1 (M+H⁺).

(S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carboxamide(Compound 183a). ¹H NMR (400 MHz, DMSO-d₆) δ 11.4 (bs, 2H), 8.98 (d,J=6.9 Hz, 1H), 7.85-7.75 (m, 1H), 7.69-7.45 (m, 8H), 4.78 (p, J=6.6 Hz,1H), 1.30 (d, J=6.7 Hz, 3H). ES/MS 451.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(5-chloro-3-(3-methoxy-4-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 184a). ¹H NMR (400 MHz, DMSO-d₆) δ 7.80 (td, J=8.0, 1.4 Hz,1H), 7.74-7.56 (m, 2H), 7.28-7.11 (m, 1H), 6.99-6.86 (m, 1H), 6.80-6.71(m, 1H), 5.10-5.01 (m, 1H), 3.79 (s, 1.2H), 3.73 (s, 1.8H), 2.27-2.11 (2s, 3H), 1.41-1.34 (m, 3H). ES/MS 478.1 (M+H⁺).

(S)-2,4-diamino-6-((1-(5-chloro-3-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 185a). ¹H NMR (400 MHz, DMSO-d₆) δ 7.82-6.85 (m, 7H),5.01-4.90 (m, 1H), 3.74 (s, 3H), 1.35 (d, J=6.6 Hz, 3H). ES/MS 463.1(M+H⁺).

(S)-2,4-diamino-6-((1-(5-chloro-3-(4-fluoro-3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 186a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (bs, 2H), 7.97-6.7 (m,6H), 5.05 (m, 1H), 3.84 (s, 3H), 1.44-1.37 (m, 3H). ES/MS 481.1 (M+H⁺).

(S)-2,4-diamino-6-((1-(5-chloro-3-(5-methoxy-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 187a-1). ¹H NMR (400 MHz, DMSO-d₆) δ 7.86-7.76 (m, 1H), 7.69(dd, J=8.2, 1.2 Hz, 1H), 7.61 (dd, J=7.8, 1.2 Hz, 1H), 7.24-7.17 (m,1H), 7.12 (d, J=2.7 Hz, 1H), 6.91 (dd, J=8.5, 2.7 Hz, 1H), 5.04 (p,J=6.6 Hz, 1H), 3.76 (s, 3H), 1.95 (s, 3H), 1.37 (d, J=6.5 Hz, 3H). ES/MS477.1 (M+H⁺).

(S)-2,4-diamino-6-((1-(5-chloro-3-(5-methoxy-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 187a-2). ¹H NMR (400 MHz, DMSO-d₆) δ 7.86-7.80 (m, 1H), 7.71(dd, J=8.2, 1.2 Hz, 1H), 7.63 (dd, J=7.8, 1.2 Hz, 1H), 7.32-7.25 (m,1H), 6.95-6.83 (m, 2H), 4.87 (p, J=6.7 Hz, 1H), 3.66 (s, 3H), 1.98-1.92(m, 3H), 1.46-1.29 (m, 3H). ES/MS 477.1 (M+H⁺).

(S)-2,4-diamino-6-((1-(5-chloro-3-(5-(difluoromethyl)-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 188a-1). ¹H NMR (400 MHz, DMSO-d₆) δ 7.79 (dt, J=10.8, 8.0 Hz,1H), 7.73-7.51 (m, 3H), 7.41-7.28 (m, 2H), 7.05 (t, J=56.4 Hz, 1H), 5.16(dd, J=8.5, 6.0 Hz, 1H), 2.08 (s, 3H), 1.35 (d, J=6.5 Hz, 3H). ES/MS497.1 (M+H⁺).

(S)-2,4-diamino-6-((1-(5-chloro-3-(5-(difluoromethyl)-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 188a-2). ¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (bs, 1H), 7.86-7.77(m, 1H), 7.72 (dd, J=8.2, 1.2 Hz, 1H), 7.62 (dd, J=7.8, 1.2 Hz, 1H),7.52 (d, J=7.3 Hz, 1H), 7.44 (d, J=6.8 Hz, 2H), 6.85 (t, J=56.0 Hz, 1H),4.77 (p, J=6.6 Hz, 1H), 2.08 (s, 3H), 1.36 (d, J=6.6 Hz, 3H). ES/MS497.1 (M+H⁺).

(S)-2,4-diamino-6-((1-(5-chloro-3-(3-(difluoromethyl)-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 189a-1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.33 (bs, 1H), 7.91-7.48(m, 3H), 7.48-7.37 (m, 2H), 7.04 (t, J=54.7 Hz, 1H), 5.28 (dt, J=13.1,6.7 Hz, 1H), 2.08 (s, 3H), 1.38 (d, J=6.5 Hz, 3H). ES/MS 497.1 (M+H⁺).

(S)-2,4-diamino-6-((1-(5-chloro-3-(3-(difluoromethyl)-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 189a-2). ¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (bs, 1H), 7.86-7.31(m, 6H), 7.16 (t, J=54.8 Hz, 1H), 4.80 (p, J=6.6 Hz, 1H), 2.09 (s, 3H),1.29 (d, J=6.6 Hz, 3H). ES/MS 497.1 (M+H⁺).

(S)-2,4-diamino-6-((1-(5-chloro-3-(3-(difluoromethyl)-5-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 190a). ¹H NMR (400 MHz, DMSO-d₆) δ 7.82 (td, J=8.0, 3.0 Hz,1H), 7.70 (ddd, J=8.1, 6.9, 1.2 Hz, 1H), 7.62 (ddd, J=7.8, 2.9, 1.2 Hz,1H), 7.38 (m, 2H), 7.15-7.02 (m, 1H), 6.83 (t, J=55.8 Hz, 1H), 5.17-4.92(m, 1H), 3.82 (s, 0.5H), 3.77 (s, 0.5H), 1.41 (d, J=6.5 Hz, 1.5H), 1.38(d, J=6.6 Hz, 1.5H). ES/MS 513.1 (M+H⁺).

(S)-2,4-diamino-6-((1-(5-chloro-3-(2,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 191a-1). ¹H NMR (400 MHz, DMSO-d₆) δ 7.78 (t, J=8.0 Hz, 1H),7.65 (dd, J=8.3, 1.2 Hz, 1H), 7.56 (dd, J=7.8, 1.1 Hz, 1H), 7.21-7.06(m, 3H), 6.71 (d, J=8.5 Hz, 1H), 6.51 (s, 2H), 6.12 (s, 2H), 4.98 (dq,J=9.1, 6.5 Hz, 1H), 2.30 (s, 3H), 1.95 (s, 3H), 1.30 (d, J=6.5 Hz, 3H).ES/MS 461.1 (M+H⁺).

(S)-2,4-diamino-6-((1-(5-chloro-3-(2,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 191a-2). ¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (bs, 1H), 7.79 (td,J=8.0, 0.9 Hz, 1H), 7.69 (dt, J=8.2, 1.1 Hz, 1H), 7.59 (dt, J=7.9, 1.1Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 7.03 (d, J=6.1 Hz, 2H), 4.81 (p, J=6.6Hz, 1H), 2.13 (s, 3H), 1.96 (s, 3H), 1.33 (d, J=6.6 Hz, 3H). ES/MS 461.1(M+H⁺).

(S)-2,4-diamino-6-((1-(5-chloro-3-(3-fluoro-5-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 192a). ¹H NMR (400 MHz, DMSO-d₆) δ 7.78 (t, J=8.0 Hz, 1H),7.65 (ddd, J=8.2, 3.4, 1.2 Hz, 1H), 7.58 (dd, J=7.8, 1.1 Hz, 1H),7.11-7.03 (m, 1H), 6.82 (m, 2H), 4.99 (d, J=6.9 Hz, 1H), 3.75 (s, 1.5H),3.69 (s, 1.5H), 1.36 (m, 3H). ES/MS 481.1 (M+H⁺).

(S)-2,4-diamino-6-((1-(5-chloro-3-(3-fluoro-5-(trifluoromethoxy)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 193a). ¹H NMR (400 MHz, DMSO-d₆) δ 7.85-7.75 (m, 1H),7.72-7.56 (m, 4H), 7.50-7.34 (m, 1H), 7.26 (bs, 2H), 4.90 (dt, J=45.4,6.8 Hz, 1H), 1.36 (m, 3H). ES/MS 535.1 (M+H⁺).

(S)-5-chloro-2-(1-((2,6-diamino-5-fluoropyrimidin-4-yl)amino)ethyl)-3-phenylquinazolin-4(3H)-one(Compound 194a)¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (bs, 1H), 7.84-7.75 (m,1H), 7.66 (dd, J=8.2, 1.2 Hz, 1H), 7.60 (dd, J=7.8, 1.2 Hz, 1H),7.56-7.51 (m, 2H), 7.50-7.40 (m, 3H), 7.37 (bs, 2H), 7.12 (bs, 1H), 4.72(t, J=6.8 Hz, 1H), 1.36 (d, J=6.7 Hz, 3H). ES/MS 426.1 (M+H⁺).

(S)-8-chloro-3-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-2-phenylisoquinolin-1(2H)-one(Compound 195a): 1H NMR (400 MHz, DMSO-d₆) δ 11.54 (brs, 1H), 7.77-7.42(m, 6H), 7.40-7.30 (m, 4H), 7.24 (brs, 2H), 6.76 (s, 1H), 4.78 (p, J=6.9Hz, 1H), 1.33 (d, J=6.8 Hz, 3H). ES/MS 442.1 (M+H⁺).

(S)-2,4-diamino-6-((1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 196a): ¹H NMR (400 MHz, DMSO-d₆) δ 8.01 (s, 1H), 7.82-7.31 (m,13 zH), 6.78 (s, 1H), 4.79 (p, J=6.5 Hz, 1H), 1.32 (d, J=6.7 Hz, 3H).ES/MS 432.1 (M+H⁺).

(S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-2-methylpropyl)amino)pyrimidine-5-carbonitrile(Compound 197a).

(S)-2,4-diamino-6-((1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylpropyl)amino)pyrimidine-5-carbonitrile(Compound 198a).

(S)-2,4-diamino-6-((1-(5-chloro-3-(3-fluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 199a-1).

(S)-2,4-diamino-6-((1-(5-chloro-3-(3-fluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 199a-2).

(S)-2,4-diamino-6-((1-(5-chloro-3-(3,5-difluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 200a-1).

(S)-2,4-diamino-6-((1-(5-chloro-3-(3,5-difluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 200a-2).

(S)-2,4-diamino-6-((1-(5-chloro-3-(5-fluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 201a-1).

(S)-2,4-diamino-6-((1-(5-chloro-3-(5-fluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 201a-2).

(S)-2,4-diamino-6-((1-(5-chloro-3-(2,3-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 202a-1).

(S)-2,4-diamino-6-((1-(5-chloro-3-(2,3-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 202a-2).

(S)-2,4-diamino-6-((1-(5-chloro-3-(4-fluoro-2,3-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 203a-2).

(S)-2,4-diamino-6-((1-(5-chloro-3-(4-fluoro-2,3-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 203a-2).

(S)-2,4-diamino-6-((1-(5-chloro-3-(3,4-difluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 204a-1).

(S)-2,4-diamino-6-((1-(5-chloro-3-(3,4-difluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 204a-2).

(S)-2,4-diamino-6-((1-(5-chloro-3-(3-fluoro-5-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrilecarbonitrile (Compound 205a).

(S)-2,4-diamino-6-((1-(5-chloro-3-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrilecarbonitrile (Compound 206a).

Example 4b Preparation of a Compound of Formula (I)

A. Preparation of a Compound of Formula (I) in which n=2, R^(1a) is F,R^(1b)═CN, m=1, R2=F, R3 is methyl, and R⁴ is cyano (Compound 154a)

To a solution of(S)-2,4-diamino-6-((1-(6-fluoro-3-(3-fluorophenyl)-8-iodo-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(560 mg, 1.0 mmol) in NMP (4 mL) was added cuprous cyanide (2.0 mmol,180 mg) and tetrakis(triphenylphosphine)Pd(0) (0.10 mmol, 120 mg). Themixture was irradiated in microwave reactor at 150° C. for one hour.Purification by flash chromatography (40 g flash silica, 30%EtOAc/Hexanes to 20% MeOH/EtOAc), followed by HPLC eluting with 5%-95%water/acetonitrile (0.1% v/v trifluoroacetic acid) provided(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-6-fluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrileas a white solid. ¹H NMR (400 MHz, DMSO) δ 8.55 (dd, J=2.8, 8.4 Hz, 1H),8.20 (dd, J=3.2, 8.0 Hz, 1H), 7.88-7.17 (m, 5H), 5.07 (m, 1H), 1.44 (d,J=6.8 Hz, 3H). ES/MS 460.1 (M+H⁺);

B. Preparation of a Compound of Formula (I), varying R¹, R², and R³; anda compound of Formula (J), varying R¹, R², R³ and R⁴

(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile(Compound 101a): ¹H NMR (400 MHz, DMSO) δ 8.48-8.42 (m, 2H), 7.87 (bs,1H), 7.77-7.73 (m, 1H), 7.74 (bs, 1H), 7.51-7.49 (m, 1H), 7.35-7.29 (m,1H), 7.08-7.05 (m, 1H), 5.15 (m, 1H), 1.48 (d, J=6.4 Hz, 3H). ES/MS460.1 (M+H⁺);

(S)-2-(1-(2,6-diamino-5-cyanopyrimidin-4-ylamino)ethyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-8-carbonitrile(Compound 122a).

(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-6-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazoline-8-carbonitrile(Compound 155a): ¹H NMR (400 MHz, DMSO) δ 8.53 (dd, J=2.8, 8.4 Hz, 1H),8.19 (dd, J=2.8, 8.0 Hz, 1H), 7.92-7.34 (m, 6H), 5.03 (m, 1H), 1.42 (d,J=6.4 Hz, 3H). ES/MS 442.1 (M+H⁺);

(S)-2,4-diamino-6-((1-(8-methoxy-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile(Compound 156a): ¹H NMR (400 MHz, DMSO) δ 7.70 (d, J=1.6 Hz, 1H), 7.68(d, J=1.6 Hz, 1H), 7.54-7.38 (m, 6H), 4.93 (m, 1H), 3.96 (s, 1H), 1.36(d, J=6.8 Hz, 3H). ES/MS 429.2 (M+H⁺);

(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-6-carbonitrile(Compound 159a): ¹H NMR (400 MHz, DMSO) δ 8.56 (dd, J=0.4, 2.0 Hz, 1H),8.25 (dd, J=2.4, 8.8 Hz, 1H), 7.86 (dd, J=0.8, 8.8 Hz, 1H), 7.83 (bs,2H), 7.66 (bs, 2H) 7.58-7.41 (m, 5H), 4.91 (m, 1H), 1.36 (d, J=6.8 Hz1H). ES/MS 424.1 (M+H⁺);

(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-3-(3-(difluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile(Compound 160a): ¹H NMR (400 MHz, DMSO) δ 8.47-8.41 (m, 2H), 8.04 (bs,2H), 7.87 (bs, 2H), 7.83-7.48 (m, 5H), 5.10 (m, 1H), 3.30 (t, J=6.8 Hz,1H), 2.18 (t, J=8.0 Hz, 1H), 1.91 (m, 1H), 1.45 (m, 3H). ES/MS 474.1(M+H⁺);

(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazoline-8-carbonitrile(Compound 161a).

Biological Examples

Activity testing was conducted in the Examples below using methodsdescribed herein and those well known in the art.

Example B1 Characterization of Compounds of Formula (I)

This Example compares the biological activity of the compounds offormula (I) and Compounds V, X, Y and Z having the following structures:

Enzymatic activity of PI3K isoforms was measured to compare the PI3Kisoform selectivity of the compounds tested, including selectivity toPI3Kδ. A cellular assay measuring basophil activation was used to assessthe potency of the compounds tested. Hepatocyte stability was alsomeasured to assess the potential half-life of the tested compounds inhuman subjects. Each of these biological experiments are described infurther detail below.

Enzymatic Activity of PI3K Isoforms

Enzymatic activity of the class I PI3K isoforms in the presence of thecompounds of Table 1 above and compounds X, Y and Z was measured using atime-resolved fluorescence resonance energy transfer (TR-FRET) assay.

The TR-FRET assay was used to monitor formation of the product3,4,5-inositol triphosphate molecule (PIP3) as it competed withfluorescently labeled PIP3 for binding to the GRP-1 pleckstrin homologydomain protein. An increase in phosphatidylinositide 3-phosphate productresults in a decrease in TR-FRET signal as the labeled fluorophore isdisplaced from the GRP-1 protein binding site.

Class I PI3K isoforms were expressed and purified as heterodimericrecombinant proteins. All assay reagents and buffers for the TR-FRETassay were purchased from Millipore. PI3K isoforms were assayed underinitial rate conditions in the presence of 25 mM Hepes (pH 7.4), and2×Km ATP (100-300 μM), 10 μM PIP2, 5% glycerol, 5 mM MgCl2, 50 mM NaCl,0.05% (v/v) Chaps, 1 mM dithiothreitol, 1% (v/v) DMSO at the followingconcentrations for each isoform: PI3K α, β, and δ at 50 picomolar (pM)and PI3Kγ at 2 nanomolar (nM). After an assay reaction time of 30minutes at 25° C., reactions were terminated with a final concentrationof 10 mM EDTA, 10 nM labeled-PIP3, and 35 nM Europium labeled GRP-1detector protein before reading TR-FRET on an Envision plate reader (Ex:340 nm; Em: 615/665 nm; 100 μs delay and 500 μs read window).

Data are normalized based on a positive (1 uM wortmanin) and negative(DMSO) controls. The α, β, δ, and γ IC₅₀ values were calculated from thefit of the dose-response curves to a four-parameter equation. IC₅₀ arereported in units of nM. These assays generally produced results within3-fold of the reported mean.

IC₅₀ values were obtained for all PI3K isoforms (α, β, δ, and γ), andTable 2 summarizes the IC₅₀ data collected for PI3Kδ in this Example B1.

Activity on Basophils

Effect on basophil activation was measured in human whole blood usingthe Flow2 CAST® kit (Buhlmann Laboratories AG, Baselstrasse,Switzerland) following the protocol provided by the manufacturer withminor modifications. Human whole blood was collected into K₂-EDTAvenipuncture tubes. Whole blood samples were treated with either DMSO(0.3% final) or a serial dilution of compounds in DMSO for 60 minutes at37° C. Basophils were then activated either with anti-FccRI mAb or withfMLP. To activate basophils using the anti-FccRI mAb; 50 μl of wholeblood was mixed with 110 μl of stimulation buffer (B-BAT-STB) and 20 μlof anti-FccRI (B-BAT-STCON). To activate basophils with fMLP; 50 μl ofwhole blood was mixed with 80 μl of stimulation buffer (B-BAT-STB) and50 μl of fMLP (B—CCR-FMLP). Stimulation buffer was used as a negativecontrol. 20 μl of the staining reagent (combination of anti-humanCD63-FITC and anti-human CCR3-PE mAbs) was then added to each tube. Thetubes were mixed gently and incubated for 25 min at 37° C. Subsequently,erythrocytes were lysed and fixed by the addition of 2 ml of lysingsolution (B-BAT-LYR) for 10 min at room temperature. Cells were pelletedby centrifugation at 1200 rpm for 10 min at room temperature in aswing-out rotor. Supernatant was aspirated and cell pellet resuspendedin 400 μl of wash buffer. Flow cytometric analysis of the basophilactivation was performed on a FC500MPL flow cytometer (Beckman CoulterInc., Fullerton, Calif.). CCR3-staining and side scatter were applied togate at least 200 basophils that expressed a high density of CCR3. Thepercent CD63 positive cells within the gated basophil population weredetermined in different treatment groups and normalized to the vehiclecontrol (0.3% DMSO) with anti-FcERI mAb of fMLP stimulus as 100%. Finalcompound concentration was adjusted to correct for dilution effect ofadded reagents. The EC₅₀ values were calculated from the analysis of thedose-response curves to a four-parameter equation. All EC₅₀ valuesrepresent geometric mean values and are reported in units of nM. Table 2below summarizes the EC₅₀ data collected from this Example B1.

Hepatocyte Stability

This assay was used to evaluate the metabolic stability of test articles(TA) following incubation in cryopreserved hepatocytes by monitoringparent drug disappearance via LC/MC. The TA with 1% final DMSOconcentration was incubated with 1 million hepatocytes/ml at 2 μMsubstrate in duplicate. The incubation was carried out at 37° C. with 5%CO₂ and saturating humidity. Samples were taken at 0, 1, 2, and 4 hoursto monitor the disappearance of TA and a half-life (t_(1/2)) wasdetermined. Table 2 below summarizes the t_(1/2) values (e.g. t_(1/2)^(a)) collected from this Example B1.

Alternatively, assay reagents and/or conditions can be modified indetermining the inhibitory activities to PI3K isomers. In additionalstudies, similar assay using TA and 0.01% final DMSO concentration wereincubated with 1 million hepatocytes/mL at 1 μM substrate in duplicate.The incubation was carried out at 37° C. with 5% CO₂ and saturatinghumidity. Samples were taken at 0, 1, 3, and 6 hours to monitor thedisappearance of TA and a half-life (t_(1/2)) was determined. Table 2below summarizes the t_(1/2) values (e.g. t_(1/2) ^(b)) collected fromthis Example B1.

The symbols used in Table 2 below are as follows:

####=<1 nM *=<1 h

###=>1 nM AND <10 nM **=>1 AND <3 h

##=>10 nM AND <50 nM ***=>3 AND <6 h

#=>50 nM ****=>6 AND <10 h

-   -   *****=>10 h

TABLE 2 human human Compound IC₅₀ EC₅₀ hepatocyte t½^(b) hepatocytet½^(a)  1a #### #### ** ****  2a #### ###  3a ### ##  4a #### ### **** 5a #### ### **  6a #### #  7a ### ####  8a #### ### ***  9a ### ### 10a ### ### *** *****  11a ### ### **** *****  12a ### ### *****  13a## ### *****  14a ### ###  15a #### #### ***  16a ### ### *** *****  17a### #### **** *****  18a #### #### ***  19a #### ### ***  20a ### ###****  21a ### ### *** ****  22a ### ### *****  23a #### ####  24a ###### ****  25a #### #### **  26a ## ### *****  27a ## ### ** *****  28a## ### *****  29a ## ### *****  30a ##  31a ### ### ****  32a ##  33a # 34a #  35a ### ### ****  36a ## ### ***** *****  37a ## ## *** **** 38a ## ### ***** *****  39a ##  40a ### ### ****  41a ### ## ***  42a## ### ** *****  43a ### ### ***  44a ## ## ** *****  45a ### #  46a ## 47a ### ### ***  48a ## # *****  49a #### #### *** *****  50a #### ####****  51a ### ### ***  52a ### ### **** *****  53a ### ## *****  54a ##### *** *****  55a #### ### ****  56a ## ### ****  57a ##  58a ### ### 59a #### ###  60a #### ####  61a ### #### *** *****  62a #### ####  63a### ### *****  64a #### ###  65a ##  66a ### ### ***  67a ### ### *******  68a #  69a ##  70a ## ###  71a ### ### ** *****  72a ## # **** 73a ### #### ***  74a ### #### ***  75a ### ## *****  76a ## # ***** 77a ### ### ** *****  78a ### ### ****  79a ##  80 #  81a ### ####  82a## # ****  83a ##  84 #  85a #  86a #  87a #  88a #  89a ### ### *********  90a ### ### ***  91a ## ## *****  92a ### #  94a #  95a ### ## 96a ### ##  97a ### ### *** *****  98a ## # ***  99a ### ## **** 100a### ### ** 101a ### ### *** ***** 102a ## ### **** 103a ## 104a #### ###*** 105a # 106a #### ### ** ***** 107a ### ### * 108a #### ### *** *****109a-1 ## 109a-2 #### ### ** 110a-1 # 110a-2 ### 111a ## # 112a ### ###***** 113a # 114a # 115a ### ## 116a ### # 117a ### ## 118a # 119a ##### 120a ### ### ** 121a ### ### *** 122a ### ### ***** ***** 124a ###### 125a ## ## 127a ### ### ** 129a #### #### 130a #### 131a ### ###132a # 133a # 135a ### ### ** 136a # 137a ### ## 138a ## 140a ### ###*** 141a ## ## 142a-1 ### ## 142a-2 ### ## 145a ### ### **** 146a ### #148a ### #### 149a ## ### **** 150a ### ### *** 151a ### ### *** 152a ##### *** 153a ### ## 154a ### ### ***** 155a ### ## ***** 156a # ## 159a# 160a ### ### *** 161a ## ## 162a # 163a ### # ** 164a ### # 165a #166a # 167a ## # 168a ### # 175a ### ### **** 176a ## ### ***** 178a ###### ***** 179a ### ### **** 181a ### #### **** 182a ### ### ***** 183a#### ## **** 184a ## # 185a #### #### ** 186a ### ## 187a-1 ### ##187a-2 ### ### 188a-1 ### ## 188a-2 #### #### ** 189a-1 ## # 189a-2 ####### 190a ### ## ** 191a-1 ### ## 191a-2 ### ### 192a ### #### ** 193a### ### ** 194a # # 195a #### ### 196a #### #### 197a #### ### *** 198a### ### 199a-1 #### #### 199a-2 ### # 200a-1 ## ## 200a-2 ## ### 201a-1#### #### 201a-2 ### ### **** 202a-1 #### ### 202a-2 ## # 203a-1 ### #203a-2 # ## 204a-1 ## 204a-2 ### 205a ### #### ** 206a #### #### X ###### ** Y #### ## * Z ### ## ** t½a: the t½ values for TA with 1% finalDMSO t½b: the t½ values for TA with 0.01% final DMSO

The results from this Example B1 demonstrate that certain compounds offormula (I) have greater activities in the cellular assay and/or greaterstability in human hepatocytes (i.e. longer half-life), for instance,than compounds X, Y, V, and Z. Table 3 below shows the t_(1/2) and EC₅₀values of Compounds 1a, 49a, 182, X, Y, V, and Z.

TABLE 3 Com- Com- Com- Com- Com- pound 1a pound 49a pound X pound Ypound Z t_(1/2) ^(a)  >9 hours  >10 hours <1 hour  <2 hours  <3 hourst_(1/2) ^(b)  >1 hour  >4 hours <2  <2 hours <2 EC₅₀ <0.5 nM <0.5 nM >5nM >15 nM >10 nM Com- Com- pound 182 pound V t_(1/2) ^(a) t_(1/2)^(b) >20 hour <1 hour EC₅₀  <2 nM >4 nM t½a: the t½ values for TA with1% final DMSO t½b: the t½ values for TA with 0.01% final DMSO.

What is claimed is:
 1. A compound having the structure of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, 2, or3; each R¹ is independently halo, cyano, unsubstituted or substitutedalkyl, unsubstituted or substituted haloalkyl, unsubstituted orsubstituted alkoxy, hydroxy, unsubstituted or substituted cycloalkyl,SO₂R^(1r), or C(O)NR^(1s)R^(1t), wherein each R^(1r), R^(1s) and R^(1t)is independently hydrogen or unsubstituted or substituted alkyl; m is 0,1, 2, or 3; each R² is independently halo, cyano, unsubstituted orsubstituted alkyl, unsubstituted or substituted haloalkyl, orunsubstituted or substituted alkoxy; and R³ is hydrogen or unsubstitutedor substituted alkyl.
 2. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R¹ is independently fluoro,chloro, cyano, methyl, CHF₂, CF₃, methoxy, or hydroxy.
 3. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein n is1 or
 2. 4. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein each R² is independently fluoro, chloro, iodo,cyano, methoxy, CHF₂, or CF₃.
 5. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein m is 1 or
 2. 6. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R³ is methyl or ethyl.
 7. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: n is 1, 2, or 3; eachR¹ is independently halo, cyano or unsubstituted or substituted alkyl; mis 1, 2, or 3; each R² is independently halo or cyano; and R³ isunsubstituted or substituted alkyl.
 8. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: n is 1; R¹ is halo; mis 2; each R² is independently halo; R³ is unsubstituted or substitutedalkyl.
 9. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the compound is the (S)-enantiomer.
 10. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein n is 2and m is 2, and the compound is of formula (IA-1):

or a pharmaceutically acceptable salt thereof, wherein: each R^(1a),R^(1b) is independently halo, cyano, unsubstituted or substituted alkyl,unsubstituted or substituted haloalkyl, unsubstituted or substitutedalkoxy, hydroxy, or unsubstituted or substituted cycloalkyl; each R^(2a)and R^(2b) is independently halo, cyano, unsubstituted or substitutedalkyl, unsubstituted or substituted haloalkyl, or unsubstituted orsubstituted alkoxy; and R³ is unsubstituted or substituted alkyl. 11.The compound of claim 10, or a pharmaceutically acceptable salt thereof,wherein: each R^(1a) and R^(1b) is independently hydrogen, halo, cyano,or unsubstituted or substituted alkyl; and each R^(2a) and R^(2b) isindependently hydrogen, halo, or cyano.
 12. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein n is 1 and m is 2,and the compound is of formula (IB-1):

or a pharmaceutically acceptable salt thereof, wherein: R^(1a) is halo,cyano, unsubstituted or substituted alkyl, or haloalkyl; each R^(2a) andR^(2b) is independently hydrogen, halo or cyano; and R³ is unsubstitutedor substituted alkyl.
 13. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein n is 1 and m is 2, and the compound isof formula (IB-4):

or a pharmaceutically acceptable salt thereof, wherein: R^(1a) is halo,cyano, unsubstituted or substituted alkyl, or haloalkyl; each R^(2a) andR^(2b) is independently hydrogen, halo or cyano; and R³ is unsubstitutedalkyl.
 14. A pharmaceutical composition comprising: a compound of claim1 or a pharmaceutically acceptable salt thereof; and at least onepharmaceutically acceptable vehicle.
 15. A compound selected from thegroup consisting of:(S)-2,4-diamino-6-((1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-hydroxy-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(8-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-chloro-8-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-chloro-3-(3-chlorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3-chlorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-chloro-3-(3-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(6-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-chloro-3-(3-cyanophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3-cyanophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3-chlorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-chloro-3-(3,5-difluorophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-chloro-3-(3-cyano-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-5,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(8-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3-cyano-5-fluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-8-fluoro-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-5,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-5,6-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-5,6-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3-cyano-5-fluorophenyl)-8-fluoro-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3-cyano-5-fluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-fluoro-3-(3-fluoro-5-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-4-oxo-8-(trifluoromethyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-5-fluoro-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-5-fluoro-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3-cyanophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(8-methyl-4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-fluoro-4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-chloro-3-(3,5-dichlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-dichlorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-chloro-3-(3-chloro-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3-chloro-5-fluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-chloro-3-(3-fluoro-5-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-fluoro-4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-chloro-3-(3-cyano-5-fluorophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5,8-dichloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-chloro-3-(3,5-dimethoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-(difluoromethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-(difluoromethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3-(difluoromethyl)-5-fluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(8-(difluoromethyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(8-(difluoromethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5,8-difluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(8-fluoro-5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-fluoro-8-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-(difluoromethyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3-cyanophenyl)-5-(difluoromethyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3-cyanophenyl)-8-fluoro-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3-(difluoromethyl)-5-fluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(8-chloro-3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-8-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-6,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-6,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(8-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(8-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-chloro-3-(3,5-difluorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5,8-dichloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-6,7-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;2,4-diamino-6-(((3-(3,5-difluorophenyl)-6,7-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3-cyanophenyl)-5-fluoro-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3-cyano-5-fluorophenyl)-5-fluoro-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;2,4-diamino-6-(((8-chloro-3-(3-cyanophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(6-chloro-3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(6-chloro-3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;(S)-5-(5-chloro-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxoquinazolin-3(4H)-yl)isophthalonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-bis(trifluoromethyl)phenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(8-chloro-3-(3,5-difluorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-(1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carboxamide;(S)-5-chloro-2-(1-(2,6-diamino-5-chloropyrimidin-4-ylamino)ethyl)-3-phenylquinazolin-4(3H)-one;(S)-2-(1-(2,6-diamino-5-chloropyrimidin-4-ylamino)propyl)-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one;(S)-2,4-diamino-6-(1-(5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carboxamide;(S)-5-chloro-2-(1-(2,6-diamino-5-(methylsulfonyl)pyrimidin-4-ylamino)ethyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;(S)-2,4-diamino-6-(1-(5-(methylsulfonyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-(1-(3-(3-(difluoromethyl)phenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-(1-(3-(3-(difluoromethyl)-5-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-(1-(5-(difluoromethyl)-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-(1-(5-chloro-3-(3-(difluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carboxamide;(S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile;(S)-2,4-diamino-6-((1-(8-chloro-3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-8-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;(S)-5-chloro-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)propyl)-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one;(S)-2,4-diamino-6-(1-(5-chloro-3-(3-(difluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-(1-(5-chloro-3-(3-isopropylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-(1-(5-chloro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;(S)-2,4-diamino-6-(1-(5-chloro-3-(3-methoxy-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile;and(S)-2,4-diamino-6-(1-(5-chloro-3-(5-fluoro-3-methoxy-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile,or a pharmaceutically acceptable salt thereof.
 16. A pharmaceuticalcomposition comprising: a compound of claim 15 or a pharmaceuticallyacceptable salt thereof; and at least one pharmaceutically acceptablevehicle.
 17. A method for treating a human, who has or is suspected ofhaving a disease or condition responsive or believed to be responsive tothe inhibition of PI3Kδ activity, comprising administering to the humana compound of claim 1 or a pharmaceutically acceptable salt thereof. 18.The method of claim 17, wherein the disease or condition is aninflammatory disorder, an autoimmune disease, or a cancer.
 19. Themethod of claim 17, wherein the disease or condition is lymphoma,multiple myeloma, or leukemia.
 20. The method of claim 17, wherein thedisease or condition is acute lymphocytic leukemia (ALL), acute myeloidleukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocyticlymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferativedisease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM),non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicularlymphoma, Waldestrom's macroglobulinemia (WM), T-cell lymphoma, B-celllymphoma, diffuse large B-cell lymphoma (DLBCL), pancreatic cancer,bladder cancer, colorectal cancer, breast cancer, prostate cancer, renalcancer, hepatocellular cancer, lung cancer, ovarian cancer, cervicalcancer, gastric cancer, esophageal cancer, head and neck cancer,melanoma, neuroendocrine cancer, CNS cancer, brain cancer, bone cancer,soft tissue sarcoma, non-small cell lung cancer, small-cell lung cancer,colon cancer, systemic lupus erythematosus (SLE), myestenia gravis,rheumatoid arthritis (RA), acute disseminated encephalomyelitis,idiopathic thrombocytopenic purpura, multiple sclerosis (MS), Sjoegren'ssyndrome, autoimmune hemolytic anemia, asthma, rheumatoid arthritis,multiple sclerosis, or lupus.